Amino acid derivatives

ABSTRACT

N-Acyl- alpha -aminocarboxylic acid derivatives of the formula &lt;IMAGE&gt; I  wherein L, R&#39; to R&#39;&#39;&#39; and Q have the definitions given in the specification, are for the treatment or prophylaxis of illnesses which are caused by the binding of adhesive proteins to blood platelets, by blood platelet aggregation and cell-cell adhesion. They are manufactured by cleaving off protecting groups in corresponding protected compounds or by converting the cyano group into the amidino group in corresponding nitriles.

This is a continuation of application Ser. No. 08/310,016, filed Sep.21, 1994, allowed which is a Rule 60 divisional of Ser. No. 07/854,135,filed Mar. 19, 1992, now U.S. Pat. No. 5,378,712.

BRIEF SUMMARY OF THE INVENTION

The invention relates to N-acyl-α-amino-carboxylic acid derivatives ofthe formula ##STR2## wherein L is a group of the formula ##STR3## R isamidino or guanidino, one of X and Y is CH and the other is CH or N, R⁰is hydrogen or amidino,

t is an integer between 2 and 6,

R', R" and R'" are hydrogen or N-substituents or side-chains usual inα-aminocarboxylic acids, whereby hydroxy or carboxy groups present inR', R" and R'" can be etherified or, respectively, esterified oramidated, and amino groups present in R', R" and R'" can be C₁₋₆-alkanoylated or aroylated, wherein R' and R" together with the N atomand C atom to which they are attached can form a 4- to 6-membered ring;

Q is a group of the formula ##STR4## or, when R' and R" together withthe N atom and C atom to which they are attached form a ring, can alsobe a group of the formula ##STR5## n is the number 0 or 1, v is aninteger between 0 and 3,

T and T' are hydrogen or a lower-alkyl or phenyl-lower-alkyl group whichis cleavable under physiological conditions,

V to V'" are hydrogen or lower-alkyl,

U and U' are hydrogen, C₁₋₆ -alkanoyl or aroyl,

AR is aryl and

R² to R⁵ are hydrogen, lower-alkyl, lower-alkoxy, halogen or a group--OCH₂ COO--T' or

R² and R³ together with the phenyl group to which they are attached forma 1-naphthyl group,

as well as hydrates or solvates and physiologically usable saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel N-acyl-α-amino acid derivatives,a process for their preparation, pharmaceutical compositions comprisingthese compounds, as well as, the use of these compounds in the controlor prevention of illnesses, such as, thrombosis, stroke, cardiacinfarct, inflammation, and arteriosclerosis. Further, these compoundsinhibit metastasis of tumour cells and can be used as antitumor agents:Further, these compounds accelerate wound healing. The compounds canalso be used in the treatment of osteoporosis.

The invention relates to N-Aroyl-α-amino-carboxylic acid derivatives ofthe formula ##STR6## wherein L is a group of the formula ##STR7## R isamidino or guanidino, one of X and Y is CH and the other is CH or N, R⁰is hydrogen or amidino,

t is an integer between 2 and 6,

R', R" and R" are hydrogen or N-substituents or side-chains usual inα-aminocarboxylic acids, whereby hydroxy or carboxy groups present inR', R" and R'" can be etherified or, respectively, esterified oramidated, and amino groups present in R', R" and R'" can be C₁₋₆-alkanoylated or aroylated, wherein R' and R" together with the N atomand C atom to which they are attached can form a 4 to 6 membered ring;

Q is a group of the formula ##STR8## or, where R' and R" together withthe N atom and C atom to which they are attached form a ring, can alsobe a group of the formula ##STR9## n is the number 0 or 1, v is aninteger between 0 and 3,

T and T' are hydrogen or a lower-alkyl or phenyl-lower-alkyl group whichis cleavable under physiological conditions,

V to V'" are hydrogen or lower-alkyl,

U and U' are hydrogen, C₁₋₆ -alkanoyl or aroyl,

Ar is aryl and

R² to R⁵ are hydrogen, lower-alkyl, lower-alkoxy, halogen or a group--OCH₂ COO--T' or

R² and R³ together with the phenyl group to which they are attached forma 1-naphthyl group,

as well as hydrates or solvates and physiologically usable saltsthereof.

In the scope of the present invention Me denotes methyl, Ac denotesacetyl, tBu denotes t-butyl, Boc denotes t-butoxycarbonyl, Z denotesbenzyloxycarbonyl, Fmoc denotes 9-fluorenylmethoxycarbonyl, Val denotesL-valyl, Phe denotes L-phenylalanyl, Ser denotes L-seryl, Gly denotesglycyl, Ala denotes L-alanyl, Asp denotes L-α-aspartyl, Leu denotesL-leucyl, Tyr denotes L-tyrosyl, Sar denotes sarcosyl, Orn denotesL-ornithyl, Lys denotes L-lysyl, Phg denotes L-α-phenylglycyl, Prodenotes L-prolyl, Glu denotes L-glutamyl, Trp denotes L-tryptophanyl.

The term "lower" denotes groups with 1-6, preferably 1-4, C atoms.Methyl, ethyl, propyl, isopropyl, n-, s- or t-butyl, hexyl and the likeare examples of lower-alkyl groups. Primary and secondary lower-alkylgroups are examples of lower-alkyl groups which are clearable underphysiological conditions. The term "alkoxy" denotes alkyl ether groupsin which the term "alkyl" has the above significance, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and thelike.

The symbols R', R" and R'" in the α-aminocarboxylic acid residue--N(R')C(R",R'")CO-- represent hydrogen or N-substituents or side-chainsusual in open-chain or cyclic, natural or synthetic α-aminocarboxylicacids. Examples of such N-substituents R' and side-chains R' and R'" arelower-alkyl optionally substituted by OH, COOH, NH₂ or aryl, especiallyby phenyl, hydroxyphenyl, hydroxyiodophenyl or hydroxyiodophenyl. Twolower-alkyl groups R' and R' optionally substituted in this manner canform a 4- to 6-membered, especially a 5-membered, ring together with theN atom and, respectively, C atom to which they are attached. Hydroxy orcarboxy groups present in the N-substituents R' and side-chains R" andR'" can be etherified or, respectively, esterified or amidated, andamino groups can be C₁₋₆ -alkanoylated or aroylated. Examples of suchether, ester and amide groups are --O--T⁰, --COO--T⁰ and respectivelyCON(V,V') in which V and V' have the above significance and T⁰ islower-alkyl, especially methyl, hexyl and tBu, or aralkyl, especiallybenzyl.

H-Gly-OH, H-Ala-OH, H-Orn-OH and H-Tyr-OH are examples of open-chainα-aminocarboxylic acids; H-Pro-OH, H-Pro(4-OH)--OH and2-piperidinecarboxylic acid are examples of cyclic α-aminocarboxylicacids, that is, those in which R' and R" together with the N atom and,respectively, C atom to which they are attached form a ring.

Formyl, acetyl and propionyl are examples of C₁₋₆ -alkanoyl groups U andU'. Aryl denotes phenyl optionally having up to 3 substituents such asalkyl, OH, lower-alkoxy, halogen or halo-lower-alkyl, especially CF₃.Aroyl denotes the corresponding benzoyl groups.

The compounds of formula I can be solvated, especially hydrated. Thehydration can be effected in the course of the manufacturing process orcan occur gradually as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I.

Examples of physiologically usable salts of the compounds of formula Iare salts with physiologically compatible mineral acids such as, forexample, hydrochloric acid, sulphuric acid or phosphoric acid; or withorganic acids such as, for example, methanesulphonic acid, acetic acid,trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaricacid, succinic acid or salicylic acid. The compounds of formula I havinga free carboxy group can also form salts with physiologically compatiblebases. Examples of such salts are alkali metal, alkaline earth metal,ammonium and alkylammonium salts such as, for example, the Na, K, Ca ortetramethylammonium salt.

The compounds of formula I can also be present in the form ofzwitterions.

The compounds of formula I which contain one or more asymmetric C atomscan exist as enantiomers, as diastereomers or as mixtures thereof, forexample, as racemates.

In formula I, R in a group L¹ is preferably amidino, X is preferably CH,Y is preferably CH or N and Q is preferably a group Q¹,Q²,Q⁴,Q⁵ or Q⁹.

In the compounds of formula I in which Q=Q¹, n is preferably 1, T ispreferably hydrogen or methyl and --N(R')C(R",R'")CO-- is preferably oneof the residues Gly, Ala, D-Ala, Val, Leu, Sar, Orn, Lys, Phg,2-methyl-Pro, Phe, Tyr, 3-iodo-Tyr, 3,5-diiodo-Tyr, Ser(Ac), Ser, Asp,Glu, Pro, 4-benzyloxy-Pro, 4-hydroxy-Pro and 2-piperidylenecarbonyl,NHCH(CH₂ CH₂ NH₂)CO, Trp, Tyr(Me), Tyr(hexyl), O,N(Me)₂ -Tyr andN(MeOCH₂ CH₂)Gly.

Preferred compounds with Q=Q², Q⁴ or Q⁵ are those with n=1, T=H; U andU'=H or Ac; Ar=α,α,α-trifluoro-m-tolyl and --N(R')C(R",R'")CO--=Ala.

Where Q=Q⁹, R² to R⁵ are preferably H or R² is carboxymethoxy ormethoxycarbonylmethoxy, T=H or CH₃ and --N(R')C (R",R'")CO--=Pro.

Examples of preferred compounds are those selected from the group of:

1-N-(p-Amidinobenzoyl)-L-alanyl!-4-piperidinyl!oxy!-acetic acid,

1- N- (5-amidino-2-pyridyl)carbonyl!-L-alanyl!-4-piperidinyl!oxy!aceticacid,

1- N-((p-amidinobenzoyl)-3-(4-hydroxy-3-iodophenyl)-L-alanyl!-4-piperidinyl!oxy!acetic acid,

1- 3-acetoxy-N-(p-amidinobenzoyl)-L-alanyl!-4-piperidinyl!oxy!aceticacid,

p- 1-(p-amidinobenzoyl)-2-pyrrolidinyl!carbonyl!Phenoxy!acetic acid,

1- N- (5-amidino-2-pyridyl)carbonyl!-L-tyrosyl!-4-piperidinyl!oxy!aceticacid and especially

1-N-(p-amidinobenzoyl)-L-tyrosyl!-4-piperidinyl!oxy!acetic acid.

Further preferred compounds of formula I are those in which Q is a groupQ³, especially in which n=O and T is hydrogen or a group Q⁷, especiallyin which T is hydrogen, and those in which Q is a group Q⁸, especiallyin which v=1, T is hydrogen or butyl and V' to V'" are hydrogen.

Examples of such compounds are:

(S)-1-2-(5-Amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyaceticacid,

ethyl (S)-1-2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate,

(S)-1-2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyaceticacid, and

1-N-(4-amidinobenzoyl)-4'-hexyloxy-L-phenylalanyl!piperidin-4-yloxy!aceticacid.

The above N-acyl-α-amino, acid derivatives can be prepared in accordancewith the invention by

a) cleaving off an ether group or a protected amino, amidino orguanidino group or a carboxylic acid ester in a compound of the formula##STR10## wherein L⁰ is a group of the formula ##STR11## in which A isan optionally protected amidino or guanidino group, R⁰¹ is an optionallyprotected amino or guanidino group, E', E", E'" and G have the samesignificance as R', R", R'" and, respectively, Q in formula I, with theproviso that where

R⁰¹ is amino or guanidino, or where A is amidino or guanidino, at leastone of E', E", E'" and G contains at least one carboxylic acid estergroup and/or ether group and/or protected amino group, or

b) convening the cyano group in a nitrile of the formula ##STR12## intothe amidino group, or c) reacting an amine of the formula

    R'--NHC(R",R")CO--Q                                        IV

with an acid of the formula L¹ -COOH or a reactive derivative thereof,and

d) if desired, functionally modifying a reactive group present in acompound of formula I, and

e) if desired, convening a compound of formula I into a physiologicallycompatible salt or converting a salt of a compound of formula I into thefree acid or base.

Examples of cleavable carboxylic acid ester groups are benzyl-OCO-- andlower-alkyl-OCO--, such as tBu-OCO--. Examples of cleavable protectedamino, amidino and guanidino groups are --NH--Z, --NH-Boc and --N₃ ;--C(NH)NH--Z, --C(NH)NH-Boc, C(N-Boc)N(Boc)₂ and --C(N-Boc)NH-Boc;--NHC(NH)NHNO₂ and --NHC(N-Boc)NH-Boc. An example of a cleavable ethergroup is tBu-O--.

Ester groups can be hydrolyzed in a known manner, for example, with abase such as an alkali metal hydroxide, for example, sodium hydroxide,in a solvent such as, for example, methanol or water; or with an acidsuch as, for example, hydro-chloric acid. Benzyl esters can be cleavedby hydrogenation in the presence of a noble metal catalyst such as, forexample, palladium on active charcoal (Pd/C) in a solvent such as, forexample, methanol, ethanol, formic acid or acetic acid at a temperatureup to about 40° C., preferably at room temperature. An amidinoprotecting group such as Z present in group A is simultaneously cleavedoff.

Ester groups such as tBu-OCO--, as well as amine and amidino protectinggroups, such as, Boc and ether groups such as tBu-O-- can be cleaved,for example, with an acid, such as, for example, formic acid ortrifluoroacetic acid, optionally in a solvent such as, for example,dichloromethane or with glycial acetic acid saturated with HCl at atemperature up to 40° C., preferably at room temperature.

Variant b) can be carried-out by convening a nitrile III by reactionwith hydrogen sulphide and triethylamine in pyridine into the thioamide,and convening this by methylation with methyl iodide in acetone andsubsequent ammonolysis with ammonium acetate in methanol into a compoundI.

The coupling c) of the amine IV, with the acid L¹ -COOH or a reactivederivative thereof such as, for example, the acid chloride is carriedout in the presence of a base, such as, for example, picoline in asolvent such as dichloromethane at a temperature up to 40° C.,preferably at room temperature.

As functional modifications of reactive groups according to processvariant d) there are to be named the cleavage of lower-alkoxycarbonylgroups --COO--T or --COO--T' or of C₁₋₆ -alkanoyloxy or aroyloxy groups--O--U or --O--U' present in group Q, or the esterification of a carboxygroup in an acid I, and the halogenation, especially the iodination, ofan aryl group present in a side-chain R" or R'".

Thus, butoxycarbonyl or methoxycarbonyl groups present in group Q can besaponified with an acid such as, for example, aqueous acetic acid oracetic acid or under basic conditions, for example, with aqueous sodiumhydroxide in methanol and acetoxy groups can be saponified withpotassium carbonate in methanol. The esterification of a carboxy groupis carried out, for example, by reaction of the acid with a suitablealcohol in the presence of catalytic amounts of H₂ SO₄.

The iodination of an aryl group, especially of the hydroxyphenyl group,in a side-chain R" or R'" can be carried out by reaction of the compoundI with Chloramine T followed by sodium iodide in water/dimethylformamide(DMF).

An amine I in which L is a group H₂ H(CH₂)_(t) is convened into thecorresponding guanidine I in which L stands for HN=C(NH₂) NH(CH₂)_(t),by reacting the amine with 2-S-isothiourea ethanesulphonate in thepresence of a base, such as, Na₂ CO₃ or NaOH at temperatures up to 40°C.

The compounds of formulas II and III are novel and as such are objectsof the present invention. They are prepared in a known manner.

Thus, a compound II in which L⁰ stands for an aryl group L⁰¹ is preparedby reacting an amine of the formula

    E'--NHC(E',E'")CO--G'                                      V

wherein G' stands for one of the groups Q¹ to Q⁹ in which the group--COO--T and an optionally present --COO--T' group are present iscarboxylic acid ester groups, with an acid of the formula ##STR13## or areactive derivative thereof, for example, the acid chloride.

This reaction can be carried out optionally in the presence oftetra-n-butylammonium hydrogen sulphate, in a solvent such as, forexample, dichloromethane and a base such as, for example, aqueous sodiumbicarbonate.

An amine H-Q⁰, wherein Q⁰ stands for one of the amino groups Q¹ to Q⁸ inwhich the group --COO--T and an optionally present --COO--T' group arepresent as carboxylic acid ester groups, can be converted with an acidof the formula ##STR14## into the nitrile III.

This reaction can be carried out in the presence of2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and an organic base such as N-methylmorpholine in a solvent suchas DMF.

A compound II in which A is amidino can be obtained by convening thecyano group into the amidino group in the nitrile corresponding to thecompound II. The latter can be prepared by coupling an amine of formulaIV above with an acid of the formula ##STR15## or with a functionalderivative thereof, for example, the acid chloride.

This coupling can be carried out in the presence of2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a base such as N-methylmorpholine in a solvent such as dichloromethane.

A compound II in which L⁰ stands for a group L⁰² with a protected aminoor guanidino group R⁰¹ is obtained by coupling an amine V with an acidof the formula R⁰¹ --(CH₂)_(t) --COOH, for example, in the presence ofHBTU and N-methylmorpholine.

A nitrile III in which Q is a group Q⁹ can be prepared, for example, asfollows:

An amine of the formula ##STR16## wherein R' and R" together with the Natom and C atom form a ring and W¹ is a protecting group, is reactedwith an acid VIII or a functional derivative thereof, the protectinggroup is cleaved off and the resulting phenol is treated with abromoacetic acid derivative BrCH₂ COO--T.

The reaction of the amine IX with the acid chloride corresponding to theacid VIII can be carried out in the presence of a base such as, forexample, triethylamine in DMF. The cleavage of a protecting group W¹,for example, benzyl, can be carried out by hydrogen-olysis over Pd/C inethanol and the reaction of the above phenol with the bromoacetic acidderivative can be carried out in DMF in the presence of potassiumcarbonate.

The amines IV and V can be prepared, for example, by coupling anN-protected amine acid of the formula

    W.sup.2 --N(E')C(E",E'")COOH                               X

with an amine H-Q⁰ and removing the protecting group W², e.g. Z or Boc,in the coupling product.

The acids VII can be prepared by coupling a functional derivative of theacid VIII, for example, the acid chloride, with an amine

    R'--NHC(R",R'")COO-nieder-Alkyl                            X'

and cleaving the ester group in the coupling product. This coupling canbe carried out, for example, in dichloromethane in the presence oftriethylamine. The lower alkyl group, for example, methyl, can beremoved with aqueous LiOH in methanol.

An amino acid of the formula

    R'--NHC(R",R'")COOH                                        X"

for example, glycine, can also be converted directly into an acid VIIusing the acid chloride corresponding to the acid VIII in the presenceof aqueous sodium bicarbonate, optionally in the presence oftetramethylammonium sulphate in dichloromethane.

An amine IX can be prepared by reacting the Grignard reagent of abromide of the formula ##STR17## with a compound of the formula##STR18## and removing the amino protecting group W² from the reactionproduct.

The amines HQ⁰, wherein Q⁰ stands for one of the amino groups Q¹ to Q⁸in which the group --COO--T and an optionally present group COO--T' arepresent as carboxylic acid ester groups, used above can be prepared asdescribed in Examples 1a)b)c), 2a), 46a)b), 47a) and 48a)b) hereinafter.

The compounds of formula I, their solvates and their salts inhibit notonly the binding of fibrinogen, fibronectin and the Willebrand factor tothe fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa), butalso the binding of these and further adhesive proteins such asvitronectin, collagen and laminin to the corresponding receptors on thesurface of different types of cell. The said compounds thereforeinfluence cell-cell and cell-matrix interactions. In particular, theyprevent the formation of blood platelet thrombi and can be used in thecontrol or prevention of illnesses such as thrombosis, stroke, cardiacinfarct, inflammation and arteriosclerosis. Further, these compoundshave an effect on tumor cells in that they inhibit their metastasis.Accordingly, they can also be used as antitumour agents. Further, theycan accelerate the healing of wounds. Since they also prevent bonedegradation, they can be used in the treatment of osteoporosis.

The inhibition of the binding of fibrinogen to the fibrinogen receptor,glycoprotein IIb/IIIa, can be demonstrated as follows:

The glycoprotein IIb/IIIa is obtained from Triton X-100 extracts ofhuman blood platelets and purified by lectin affinity chromatography(Analytical Biochemistry 151, 1985, 169-177) and chromatography on anArg-Gly-Asp-Ser affinity column (Science 231, 1986, 1559-62). Thethus-obtained receptor protein is bonded to microtitre plates. Thespecific binding of fibrinogen to the immobilized receptor is determinedwith the aid of an ELISA system ("enzyme linked immunosorbent assay").The IC₅₀ values hereinafter correspond to that concentration of the testsubstance which is required to inhibit the binding of fibrinogen to theimmobilized receptor by 50%:

    ______________________________________                                        Product of                                                                    Example                                                                              1      3       4    5    6    7     8    9                             ______________________________________                                        IC.sub.50 (mM)                                                                       0.01   0.0017  0.14 0.001                                                                              0.027                                                                              0.033 0.008                                                                              0.08                          ______________________________________                                        Product of                                                                    Example                                                                              10     13      14   15   16   18    21   22                            ______________________________________                                        IC.sub.50 (mM)                                                                       0.017  0.001   0.018                                                                              0.053                                                                              0.002                                                                              0.0017                                                                              0.16 0.47                          ______________________________________                                        Product of                                                                    Example                                                                              24     27      30   37    39    40    41                               ______________________________________                                        IC.sub.50 (mM)                                                                       0.026  0.008   0.015                                                                              0.0003                                                                              0.0008                                                                              0.05  0.0007                           ______________________________________                                        Product of                                                                    Example                                                                              42     43      44                                                      ______________________________________                                        IC.sub.50 (mM)                                                                       0.007  0.0016  0.01                                                    ______________________________________                                    

These compounds have low toxicity. Thus, the products of Examples 3 and14 have a LD₅₀ of 250 and the product of Example 5 an LD₅₀ of 500 mg/kgi.v. in the mouse.

As mentioned earlier, medicaments containing a compound of formula I, asolvate thereof or a salt thereof are an object of the presentinvention. The medicaments can be administered enterally, for example,orally, in the form of tablets, coated tablets, dragees, hard and softgelatin capsules, solutions, emulsions or suspensions, or rectally, forexample, in the form of suppositories; or as a spray. The administrationcan, however, also be effected parenterally, for is example, in the formof injection solutions or as an infusion.

The active ingredient can be mixed with pharmaceutically inert,inorganic or organic excipients for the preparation of tablets, coatedtablets, dragees and hard gelatin capsules. Lactose, maize starch orderivatives thereof, talc, stearic acid or its salts can be used, forexample, as such excipients for tablets, dragees and hard gelatincapsules. Suitable excipients for soft gelatin capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like; depending on the nature of the active ingredient no excipientsare, however, generally required in the case of soft gelatin capsules.Suitable excipients for the preparation of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar and glucose and thelike; suitable excipients for injection solutions are, for example,water, alcohols, polyols, glycerol and vegetable oils and the like.Suitable excipients for suppositories are, for example, natural orhardened oils, waxes, fats and semi-liquid or liquid polyols and thelike. The pharmaceutical preparations can, moreover, containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colourants, flavorants, salts for varying the osmoticpressure, buffers, coating agents or antioxidants.

For the control or prevention of the illnesses referred to above, thedosage of the active ingredient can vary within wide limits and will, ofcourse, be fitted to the individual requirements in each particularcase. In general, in the case of oral administration a dosage of about0.1 to 20 mg/kg, preferably of about 0.5 to 4 mg/kg, per day should beappropriate for adults, although the upper limit just given can beexceeded when this is shown to be indicated.

EXAMPLE 1

A solution of 2.43 g of t-butyl 1-N-(p-amidinobenzoyl)-glycyl!-4-piperidinyl!-oxy!acetate in 15 ml ofdichloromethane/trifluoroacetic acid 1:1 is left to stand at roomtemperature for 5 hours. After evaporation of the solvent andchromatography. silylated silica gel (LiChroprep RP-18), methanol/watergradient! there is obtained 0.46 g of the trifluoroacetate of 1-N-(p-amidinobenzoyl)glycyl!-4-piperidinyl!oxy!acetic acid, m.p.233°-236° C. MS (FAB): 363 (M+H)⁺.

The starting material can be prepared as follows:

a) 69.1 ml of triethylamine and 70.2 ml of benzyl chloroformate areadded in succession at 0° C. to a solution of 50 g of4-hydroxypiperidine in 500 ml of dichloromethane. The resultingsuspension is stirred at room temperature overnight and subsequentlyfiltered. The residue which separates after concentration of thefiltrate is taken up in ethyl acetate, washed with water and 1Nhydrochloric acid, dried and concentrated. There are obtained 73.6 g ofN-benzyloxycarbonyl-4-hydroxy-piperidine, R_(f) =0.56 (ethylacetate/methanol 9:1), MS (EI): 235 (M⁺).

b) 28 ml of t-butyl bromoacetate and 1.4 g of tetra-n-butylammoniumhydrogen sulphate in 10 ml of water are added to a solution of 30.1 g ofN-benzyloxycarbonyl-4-hydroxy-piperidine in 300 ml of toluene.Thereafter, a solution of 125 g of sodium hydroxide in 125 ml of wateris added dropwise thereto. After stirring overnight, the organicextracts are separated, dried and concentrated. After drying there areobtained 34.1 g of N-benzyloxycarbonyl-4- (t-butoxy carbonyl)methoxy!-piperidine, R_(f) =0.76 (ethyl acetate). MS (EI): 293 (M-C₄H₈)⁺.

c) 1.5 g of Pd/C (10%) are added to a solution of 30 g of the productfrom b) in 50 ml of ethanol. The reaction mixture is hydrogenated atroom temperature. Thereafter, the catalyst is filtered off, washed withethanol and the filtrate is concentrated. There are obtained 17.4 g oft-butyl-4-piperidinyloxyacetate, R_(f) =0.14 (ethyl acetate/methanol1:1). MS (EI): 215 (M⁺).

d) 5.8 g of Z-glycine are first activated with 5.4 g of CDMT and thencoupled with 6.0 g of t-butyl 4-piperidinyloxyacetate and 6.3 ml ofN-methylmorpholine in dichloromethane there are obtained 10 g of benzyl4- (t-butoxycarbonyl)methoxy!piperidinyl!carbonyl!methyl!carbamate. MS(EI): 406 (M⁺).

e) By hydrogenolyzing solution of 10 g of the product from d) in 200 mlof ethanol in the presence of 0.7 g of Pd/C (10%) and 1.4 ml of aceticacid there are isolated, after chromatography on silica gel with ethylacetate/methanol 1:1, 4.1 g of t-butyl 1-(1-glycyl-4-piperidinyl)oxy!acetate, MS (EI): 273 (M+H⁺). IR: 1746 cm⁻¹.

f) 2.95 g of p-amidinobenzoyl chloride hydrochloride (prepared fromp-amidinobenzoic acid by reaction with thionyl chloride in THF in thepresence of DMF) are added at room temperature to a mixture of 4.1 g ofthe product from e) and 0.03 g of tetra-n-butylammonium hydrogensulphate in 210 ml of dichloromethane/saturated sodium hydrogencarbonate solution 4:3. After stirring overnight, the mixture is dilutedwith dichloromethane and water, adjusted to pH 9-10 by the addition of1N sodium hydroxide solution, the organic extracts are separated, driedand concentrated. After drying, there are obtained 2.43 g of the desiredstarting material, MS (FAB): 419 (M+H)⁺.

EXAMPLE 2

A) A solution of 1.5 g of methyl 1-N-(p-cyanbenzoyl)glycyl!-4-piperidinyl!oxy!acetate in 215 ml ofpyridine/triethylamine 40:3 is saturated with hydrogen sulphide and leftat room temperature for 24 hours. After removing the solvent, theresidue is taken up in ethyl acetate and washed with saturated sodiumchloride solution. The organic extracts are dried and concentrated.After chromatography of the residue on silica gel with ethyl acetatefollowed by ethyl acetate/methanol, there are isolated 1.34 g of methyl1- N- p-(thiocarbamoyl)benzoyl!-glycyl!-4-piperidinyl!oxy!acetate, MS(FAB): 394 (M+H)⁺.

B) The reaction of 1.25 g of the product of the preceding step with 7.5ml of methyl iodide in 150 ml of acetone at boiling temperature gives,after filtration and removal of the solvent, 1.65 g of methyl 1- N- p-1-(methylthio)formimidoyl!benzoyl!-glycyl!-4-piperidinyl!oxy!acetatehydroiodide, MS (FAB): 408 (M+H)⁺.

C) By ammonolysis of 1.5 of the product from B) in the presence of 0.32g of ammonium acetate in 100 ml of methanol at boiling temperature thereis obtained 0.76 g of methyl 1- N-p-amidinobonzoyl)glycyl!-4-piperidinyl!oxy!acetate hydroiodide. M.p.103°-105° C. MS (FAB: 377 (M+H)⁺.

The nitrile starting material can be prepared as follows:

a) By esterifying the trifluoroacetate of 4-piperidinyloxy-acetic acid(prepared by treating the product of Example 1c) with trifluoroaceticacid in dichloromethane) in methanol in the presence of thionyl chloridethere is obtained methyl 4-piperidinyloxyacetate hydrochloride, MS (EI):173 (M)⁺.

b) The coupling of 1.35 g of the product from a) with 1.18 g ofN-(p-cyanobenzoyl)glycine (prepared by reacting glycine withp-cyanobenzoyl chloride in saturated sodium hydrogen carbonate solution)in the presence of HBTU and N-methylmorpholine in DMF yields, afterchromatography on silica gel (ethyl acetate/methanol 9:1 to 1:1), 1.66 gof the desired starting nitrile, MS (EI): 359 (M)⁺.

EXAMPLE 3

From 13 g of t-butyl 1-N-(p-amidinobenzoyl)-L-alanyl!-4-piperidinyl!oxy!acetate there areobtained by treatment with trifluoroacetic acid in dichloromethane (asdescribed in Example 1), after recrystallization from methanol/diethylether, 8.9 g of the trifluoroacetate of 1-N-(p-amidinobenzoyl)-L-alanyl!-4-piperidinyl!oxy!acetic acid. m.p. 120°C. (decomposition). MS (FAB): 377 (M+H)⁺. α!_(D) ²⁰ =+24.7° (c=0.7,water).

The starting-material can be prepared as follows:

a) Coupling of 18 g Z-L-alanine with 17.4 g t-butyl4-piperidinyloxyacetate and subsequent hydrogenolysis of the productobtained as in Example 1d) and e) gives 15.8 g of the acetate of t-butyl1- (1-L-alanyl-4-piperidinyl)oxy!acetate. M.p. 93°-96° C. α!_(D) ²⁰=+2.0° (c+1.0 methanol).

b) The coupling of 4.7 g of the product from a) with 3.4 g ofp-amidinobenzoyl chloride hydrochloride as in Example 1f) gives 4.2 g ofthe desired starting material. MS (EI): 433 (M+H)⁺.

EXAMPLE 4

From 0.3 g of t-butyl 1-N-(t-butoxycarbonyl)amidinobenzoyl!-D-alanyl!-4-piperidinyl!oxy!acetatethere is obtained in analogy to Example 1 0.1 g of 1-N-(p-amidinobenzoyl)-D-alanyl!-4-piperidinyl!oxy!acetic acid as thetrifluoroacetate. M.p. 115° C. (decomposition). α!_(D) ²⁰ =-27.5°(c=0.8, water). MS (FAB): 377 (M+H)⁺.

The starting material can be prepared as follows:

a) By reacting 3 g of t-butyl 4-piperidinyloxyacetate with 2.43 g ofZ-D-alanine as described in Example 1d) there are obtained, afterchromatography on silica gel with ethyl acetate/hexane 1:1, 3.1 g ofbenzyl (R)-1- 4-(t-butoxycarbonyl)methoxy!piperidinyl!carbonyl!ethyl!carbamate. MS (EI):420 (M)⁺.

b) By hydrogenolyzing 3.1 g of the product, from a) as described inExample 1e) there are obtained 2.5 g of the acetate of t-butyl 1-(1-D-alanyl-4-piperidinyl)oxy!acetate, MS (EI): 215 (M-C₃ H₅ NO).

c) By reacting 1 g of the product of the previous stage with 0.66 g ofp-amidinobenzoyl chloride hydrochloride in DMF in the presence oftriethylamine and subsequently treating with di-t-butyl dicarbonatethere is obtained, after chromatography on silica gel withdichloromethane/methanol 20.1, 0.3 g of the desired starting material:MS (FAB): 533 (M+H)⁺.

EXAMPLE 5

By hydrolyzing 1.6 g of t-butyl 1- N-(5-amidino-2-pyridyl)carbonyl!-L-alanyl!4-piperidinyl!oxy!acetate inglacial acetic acid saturated with hydrogen chloride there is obtained,after chromatography on silylated silica gel RP-18 and recrystallizationfrom-THF/ethyl acetate, 0.15 g of 1- N-(5-amidino-2-pyridyl)carbonyl!-L-alanyl!4-piperidinyl!oxy!acetic acid.M.p. above 200° C. (decomposition). MS (FAB): 378 (M+H)⁺.

The starting material can be prepared as follows:

a) By reacting 2.4 g of the acetate of t-butyl 1(1-L-alanyl-4-piperidinyl)oxy!acetate (Example 3a)) with 1.0 g of5-cyano-2-picolinic acid in accordance with Example 1d) there areobtained 2.43 g of t-butyl 1- N-(5-cyano-2-pyridyl)carbonyl!-L-alanyl!-4-piperidinyl!oxy!acetate, MS(FAB): 417 (M+H)⁺.

b) The sequential treatment of 2.4 g of the product of the previousstage as described in Example 2A) B) C) yields 2 g of the desiredstarting material. M.p. 142°-145° C. MS (FAB): 434 (M+H)⁺.

EXAMPLE 6

From 1 g of the acetate of t-butyl 1- N-(p-amidino-benzoyl)L-valyl!-4-piperidinyl!oxy!acetate there is obtained, in analogy toExample 1, after crystallization from ethyl acetate, 0.8 g of 1-N-(p-amidinobenzoyl)-L-valyl!-4-piperidinyl!oxy!-acetic acid as thetrifluoroacetate. M.p. 210°-211° C. MS (FAB): 405 (M+H⁺). α!_(D) ²⁰=+32.6° (c=0.8, water).

The starting material can be prepared as follows:

a) By coupling 2.5 g of Z-L-valine with 2 g of t-butyl4-piperidinyloxyacetate as described in Example 2b) there are obtained 4g of t-butyl 1- N-(benzyloxy)carbonyl!-L-valyl!-4-piperidinyl!oxy!acetate, MS (EI): 449(M+H)⁺.

b) In analogy to Example 1e), but without the addition of acetic acid,from 1.9 g of the product of Example 6a) there are obtained 1.4 g oft-butyl 1- (1-L-valyl-4-piperidinyl)oxy!-acetate, MS (EI): 315 (M+H)⁺.

c) In analogy to Example 1f), from 3.3 g of the product of Example 6b)and 2.5 g of p-amidinobenzoyl chloride hydro-chloride there areobtained, after chromatography. (silica gel;dichloromethane/methanol/acetic acid 95:4:1) and crystallization fromdiethyl ether, 1.1 g of the desired acetate starting material. M.p.179°-182° C. MS (FAB): 461 (M+H)⁺.

EXAMPLE 7

From 1.5 g of the acetate of t-butyl 1-N-(p-amidinobenzoyl)-L-leucyl!-4-piperidinyl!oxy!acetate there areobtained in analogy to Example 1, after crystallization from ethylacetate/diethyl ether, 1.1 g of 1-N-(p-amidinobenzoyl)-L-leucyl!-4-piperidinyl!oxy!acetic acid as thetrifluoroacetate. M.p. 216°-218° C. MS (FAB): 419 (M+H)⁺. α!_(D) ²⁰=+22.5° (c=0.8, water).

The acetate starting material can be prepared as follows:

a) By coupling 2.6 g of Z-L-leucine with 2 g of t-butyl4-piperidinyloxyacetate as described in Example 1d) there are obtained4.1 g of t-butyl 1- N-(benzyloxy)carbonyl!-L-leucyl!-4-piperidinyl!oxy!acetate, MS (FAB): 463(M+H)⁺.

b) In analogy to Example 6b) and 1f), from 4.1 g of the product ofExample 7a) there are obtained, after chromatography (silica gel;dichloromethane/methanol/acetic acid 95:4:1) and crystallization fromdiethyl ether, 1.5 g of the desired acetate. M.p. 120°-129° C.(decomposition). MS (FAB): 475 (M+H)⁺.

EXAMPLE 8

From 1.4 g of the acetate of t-butyl 1-(p-amidino-N-methylbenzamido)acetyl!-4-piperidinyl!oxy!acetate there isobtained, in analogy to Example 1, after crystallization from diethylether, 0.9 g of 1-(p-amidino-N-methylbenzamido)-acetyl!-4-piperidinyl!oxy!acetic acid asthe trifluoroacetate. M.p. 134°-135° C. MS (FAB): 377 (M+H)⁺.

The starting material can be prepared as follows:

a) By coupling 2.0 g of Z-sarcosine N-hydroxysuccinimide ester with 1.3g of t-butyl 4-piperidinyloxyacetate in the presence of triethylamine inTHF there are obtained 2.1 g of benzyl 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!- methyl!methylcarbamate.MS (FAB): 421 (M+H)⁺.

b) In analogy to Example 6b) and 1f), from 4 g of the product of Example8a) there are obtained, after chromatography (silica gel;dichloromethane/methanol/acetic acid 93:5:2) and crystallization fromdiethyl ether, 1.5 g of the desired acetate. M.p. 188°-189° C. MS (FAB):432 (M+H)⁺.

EXAMPLE 9

From 5.4 g of t-butyl 1- N² -(p-amidinobenzoyl)-N⁵-(t-butoxycarbonyl)-L-ornithyl!-4-piperidinyl!oxy!acetate there areobtained in analogy to Example 1 4.9 g of 1- N²-(p-amidinobenzoyl)-L-ornithyl!-4-piperidinyl!oxy!acetic acid as thetrifluoroacetate. MS (FAB): 420 (M+H)⁺. α!_(D) ²⁰ =+4.5° (c=0.8, MeOH).

The starting material can be prepared as follows:

a) By reacting 6 g of 4-piperidinyloxyacetate with 10.2 g of N² -Z-N⁵-Boc-L-ornithine as described in Example 1d) there are obtained, afterchromatography on silica gel with ethyl acetate/hexane 1:1, 11 g oft-butyl 1- N₂ -(benzyloxycarbonyl)-N⁵-(t-butoxycarbonyl)-L-ornithyl!-4-piperidinyl!oxy!acetate. MS (FAB): 564(M+H)⁺.

b) By hydrogenolyzing 11 g of the product of a) as described in Example1e), there are obtained 9 g of the acetate of t-butyl 1- N⁵-(t-butoxycarbonyl)-L-orinthyl!-4-piperidinyl!oxy!acetate. MS (FAB): 430(M+H)⁺.

c) By reacting 9 g of the product of b) with 4.4 g of p-amidinobenzoylchloride hydrochloride as described, in Example 1f), there are obtained5.7 g of the desired starting material. MS (FAB): 576 (M+H)⁺.

EXAMPLE 10

From 0.54 g of t-butyl 1- N₂ - p-N-(t-butoxycarbonyl)amidinobenzoyl!-N⁶-(t-butoxycarbonyl)-L-lysyl!-4-piperidinyl!oxy!acetate there is obtainedin analogy to Example 1, 0.35 g of 1- N²-(p-amidinobenzoyl)-L-lysyl!-4-piperidinyloxy!acetic acid as thetrifluoroacetate. MS (FAB): 434 (M+H)⁺. α!_(D) ²⁰ =+12.4° (c=0.8,water).

The starting material can be prepared as follows:

a) By reacting 2 g of t-butyl 4-piperidinyloxyacetate with 2.8 g of N²-Z-N⁶ -Boc-L-lysine as described in Example 1d), there are obtained,after chromatography on silica gel with ethyl acetate/hexane 1:1, 2.6 gof t-butyl 1- N² -(benzyloxycarbonyl)-N⁶-(t-butoxycarbonyl)-L-lysyl!-4-piperidinyl!oxy!acetate. MS (FAB): 578(M+H)⁺.

b) By hydrogenolyzing 2.6 g of the resulting product as described inExample 1e), there are obtained 2 g of the acetate of t-butyl 1- N⁶-(t-butoxycarbonyl)-L-lysyl!-4-piperidinyl!oxy!-acetate, MS (FAB): 444(M+H)⁺.

c) By reacting 2 g of the product of the previous step with 1 g ofp-amidinobenzoyl chloride hydrochloride as described in Example 4c),there are obtained, after chromatography (silica gel;dichloromethane/methanol 20:1), 1.95 g of the desired starting material.MS (FAB): 690 (M+H)⁺.

EXAMPLE 11

From 0.4 g of the acetate of t-butyl 1-N-(p-amidinobenzoyl)-L-phenylglycyl!-4-piperidinyl!oxy!acetate there isobtained in analogy to Example 1, 0.25 g of 1-N-(p-amidino-benzoyl)-L-phenylglycly!4-piperidinyl!oxy!acetic acid asthe trifluoroacetate. M.p. above 250° C. (ethyl acetate/diethyl ether1:1), MS (FAB): 439 (M+H)⁺. α!_(D) ²⁰ =+6.5° (c=0.6, MeOH).

The starting material can be prepared as follows:

a) By reacting 1.85 g of t-butyl 4-piperidinyloxyacetate with 3.5 g ofZ-L-phenylglycine N-hydroxysuccinimide ester, as described in Example8a), there are obtained, after chromatography on silica gel withpetroleum ether/diethyl ether 1:1, 3.8 g of t-butyl1-(N-benzoyloxycarbonyl-L-phenylglycyl)-4-piperidinyl!oxy!acetate. MS(FAB): 349 (M+H)⁺.

b) By hydrogenolyzing 4.7 g of the resulting product as described inExample 6b), there are obtained 3.2 g of1-(L-phenylglycyl)-4-piperidinyl!oxy!acetate. MS (FAB): 349 (M+H)⁺.

c) By reacting 3.2 g of the product of the previous step with 2.2 g ofp-amidinobenzoyl chloride hydrochloride as described in Example 1f),there is obtained, after chromatography (silica gel;dichloromethane/methanol/acetic acid 95:5:2), 0.4 g of the desiredacetate. M.p. 207°-220° C. (ethyl acetate, decomposition). MS (FAB): 495(M+H)⁺.

EXAMPLE 12

From 0.5 g of the acetate of t-butyl- 1-1-(p-amidinobenzoyl)-2-methyl-L-prolyl!-4-piperidinyl!oxy!acetate thereis obtained, in analogy to Example 1, 0.14 g of 1-1-(p-amidinobenzoyl)-2-methyl-L-prolyl!-4-piperidinyl!oxy!acetic acid asthe trifluoroacetate. M.p. 219°-220° C. (acetonitrile). MS (FAB): 417(M+H)⁺. α!_(D) ²⁰ =+17.1° (c=0.9, MeOH).

The acetate starting material can be prepared as follows:

a) By reacting 2-methyl-L-proline hydrobromide with p-cyanobenzoylchloride analogously to Example 2b) there is obtained1-(p-cyanobenzoyl)-2-methyl-L-proline. MS (EI): 213 (M-COOH)⁺.

b) By reacting 1.67 g of t-butyl 4-piperidinyloxyacetate with 0.8 g ofthe acid chloride of 1-(p-cyanobenzoyl)-2-methyl-L-proline (obtained bytreating the product of the previous step with thionyl chloride) thereis obtained 0.89 g of t-butyl 1-1-(p-cyanobenzoyl)-2-methyl-L-prolyl!-4-piperidinyl!oxy!acetate. M.p.180°-182° C. (ethyl acetate).

c) By sequentially treating 0.89 g of the product of b), as described inExample 2A)B)C), there is obtained, after chromatography (silylatedsilica gel RP-18; water/methanol 9:1), 0.59 g of the desired acetate.M.p. 191°-192° C. (ethyl acetate, decomposition). MS (FAB): 473 (M+H)⁺.

EXAMPLE 13

From 2.5 g of the acetate of t-butyl 1-N-(p-amidinobenzoyl)-3-phenyl-L-alanyl!-4-piperidinyl!oxy!acetate, thereare obtained, in analogy to Example 1, 1.9 g of 1-N-(p-amidinobenzoyl)-3-phenyl-L-alanyl!-4-piperidinyl!oxy!acetic acid asthe trifluoroacetate. M.p. 234°-235° C. (ethyl acetate). α!_(D) ²⁰=17.9° (c=1.0, MeOH). MS (EI): 453 (M+H)⁺.

The acetate starting material can be prepared as follows:

a) By reacting 2.15 g of t-butyl 4-piperidinyloxyacetate with 3.0 g ofZ-L-phenylalanine, as described in Example 2b), there are obtained 4.8 gof t-butyl1-(N-benzyloxycarbonyl-3-phenyl-L-alanyl)-4-piperidinyl!oxy!acetate MS(FAB): 497 (M+H)⁺.

b) By hydrogenolyzing 4.8 g of resulting product as described in Example6b) and subsequently reacting with 2.0 g of p-amidinobenzoyl chloridehydrochloride as described in Example 1f), there are obtained, afterchromatography (silica gel dichloromethane/methanol/acetic acid 22:2:1)2.5 g of the desired acetate. M.p. 176°-178° C. (diethyl ether). MS(FAB): 509 (M+H)⁺.

EXAMPLE 14

From 2.5 g of the acetate of t-butyl 1-N-(p-amidinobenzoyl)-3-(p-t-butoxyphenyl)-L-alanyl!-4-piperidinyl!oxy!-acetatethere is obtained in analogy to Example 1, after chromatography(silylated silica gel RP-18, water/methanol gradient), 1.0 g of 1-N-(p-amidinobenzoyl)-L-tyrosyl!-4-piperidinyl!oxy!acetic acid as thetrifluoroacetate. M.p. 125°-130° C. (ethyl acetate, decomposition). MS(FAB): 469 (M+H)⁺.

The acetate starting material can be prepared as follows:

a) By reacting 2.15 g of t-butyl 4-piperidinyloxyacetate with 3.71 g ofN-Z-(OtBu)-L-tyrosine as described in Example 2b) there are obtained,after chromatography (silica gel; diethyl ether/petroleum ether 1:1),4.8 g of t-butyl 1- N-(benzyloxy-carbonyl)-3-p-(t-butoxyphenyl)!-L-alanyl!-4-piperidinyl!oxy!-acetate. M.p. 96° C.(diethyl ether), MS (EI): 417 (M-C₇ H₇ -C₄ H₈)⁺, α!_(D) ²⁰ =+5.4°(c=0.8, CH₃ OH),

b) By hydrogenolyzing 4.8 g of the product of the previous step as inExample 6b) and subsequently reacting with 1.5 g of p-amidinobenzoylchloride hydrochloride, as in Example 1f), there are obtained, afterchromatography (silica gel; dichloromethane/methanol/acetic acid22:2:1), 2.6 g of the desired acetate. M.p. 170°-172° C. (diethylether). MS (FAB): 581 (M+H)⁺.

EXAMPLE 15

0.09 g of the trifluoroacetate of methyl 1-N-(p-amidinobenzoyl)-L-tyrosyl!-4-piperidinyl!oxy!acetate is isolated asa byproduct of the chromatography described in Example 14. M.p.189°-190° C. (ethyl acetate). MS (FAB): 483 (M+H)⁺.

EXAMPLE 16

By reacting 0.58 g of the trifluoroacetate of 1-N-(p-amidinobenzoyl)-L-tyrosyl!-4-piperidinyl!oxy!acetic acid (Example14 with Chloramine T followed by sodium iodide in water/DMF 8:1 there isobtained, after chromatography (silylated silica gel RP-18water/acetonitrile gradient), 0.04 g of 1-N-(p-amidinobenzoyl)-3-(4-hydroxy-3-iodophenyl)-L-alanyl!-4-piperidinyl!oxy!aceticacid. M.p. 230° C. (water, decomposition). MS (FAB): 595 (M+H)⁺.

EXAMPLE 17

0.09 g of 1-N-(p-amidinobenzoyl)-3-(4-hydroxy-3,5-diiodophenyl)-L-alanyl!-4-piperidinyl!oxy!aceticacid is also isolated from the reaction described in Example 16. M.p.220°-221° C. (water, decomposition). MS (FAB): 720 (M+H)⁺.

EXAMPLE 18

From 1.3 g of t-butyl 1- 3-t-butoxy-N- p- N-(t-butoxycarbonyl)amidino!benzoyl!-L-alanyl!-4-piperidinyl!oxy!-acetate bytreatment with hydrogen chloride in glacial acetic acid there isobtained, after chromatography (silylated silica gel RP-18,methanol/water gradient) 0.45 g of the hydrochloride of 1-3-acetoxy-N-(p-amidinobenzoyl)-L-alanyl!-4-piperidinyl!-oxy!acetic acid,α!_(D) ²⁰ =+0.9° (c=1.0, MeOH). MS (FAB): 435 (M+H)⁺.

The starting material can be prepared as follows:

a) By coupling 7.5 g of Z-L-Ser(tBu)-OH with 1.0 g of t-butyl4-piperidinyloxyacetate and subsequently hydrogenolyzing the resultingproduct, as described in Example 1d)e), there are obtained 10.6 g of theacetate of t-butyl 1-(3-t-butoxy-L-alanyl)-4-piperidinyl!oxy!acetate.M.p. 76°-78° C. MS (FAB): 359 (M+H)⁺.

b) By reacting-9.9 g of the product of the previous step with 5.2 g ofp-amidinobenzoyl chloride hydrochloride in DMF in the presence oftriethylamine and subsequently treating with di-t-butyl dicarbonatethere are obtained, after chromatography on silica gel withdichloromethane/methanol 20:1 followed by ethyl acetate/hexane 3:1, 4.3g of t-butyl 1- 3-t-butoxy-N- p-N-(t-butoxycarbonyl)amidinobenzoyl!-L-alanyl!-4-piperidinyl!oxyacetate.M.p. 162°-165° C. MS (FAB): 605 (M+H)⁺.

EXAMPLE 19

From 1.0 g of t-butyl 1- 3-t-butoxy-N- p-N-(t-butoxycarbonyl)amidino!benzoyl!-L-alanyl!-4-piperidinyl!oxy!acetate(Example 18) there is obtained in analogy to Example 1, afterchromatography (silylated silica gel RP-18, water), 0.58 g of thetrifluoroacetate of 1-N-(p-amidinobenzoyl)-L-seryl!-4-piperidinyl!oxy!acetic acid. α!_(D) ²⁰=+17.6° (c=1.0, water). MS (FAB): 393 (M+H)⁺.

EXAMPLE 20

From 5 g of L-N-(p-amidinobenzoyl)-3- 4-(t-butoxycarbonyl)methoxy!piperidinyl!carbonyl-β-alanine t-butyl esterthere are obtained in analogy to Example 1, after crystallization usingethyl acetate/THF, 2.0 g of the trifluoroacetate ofL-N-(p-amidinobenzoyl)-3-4-(carboxymethoxy)piperidino!carbonyl!-β-alanine, m.p. 145°-150° C. MS(FAB): 421 (M+H)⁺.

The starting material can be prepared as follows:

a) By coupling 11 g of the monohydrate of Z-L-Asp(O-tBu)-OH with 7.0 gof t-butyl 4-piperidinyloxyacetate as described in Example 2b), thereare obtained 16 g of L-N-(benzyloxy-carbonyl)-3- 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!-β-alanine t-butyl ester.MS (FAB): 521 (M+H)⁺.

b) After hydrogenolyzing 17 g of the product of the previous step, as inExample 6b), there are isolated 11 g of L-3- 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!- -β-alanine t-butylester. MS (FAB): 387 (M+H)⁺.

c) By coupling 11 g of the product of the previous step with 6.9 g ofp-amidinobenzoyl chloride hydrochloride, as in Example 1f), there areisolated, after chromatography (silica gel, dichloromethane/methanol9:1), 10.2 g. of the desired starting material. MS (FAB): 533 (M+H)⁺.

EXAMPLE 21

From 0.5 g of t-butyl 1-N-(p-amidinobenzoyl)-4-t-butoxy-L-glutamoyl!-4-piperidinyl!oxy!acetatethere is obtained, in analogy to Example 1, after crystallization usingethyl acetate, 0.25 g of the trifluoroacetate of 1-N-(p-amidinobenzoyl)-L-α-glutamoyl!-4-piperidinyl!oxy!acetic acid. M.p.105°-108° C. α!_(D) ²⁰ =+6.9° (C=0.8, methanol). MS (FAB): 435 (M+H)⁺.

The starting material can be prepared as follows:

a) By coupling 11 g of Z-L-GIu(Ot-Bu)-OH with 7.0 g of t-butyl4-piperidinyloxyacetate, as described in Example 1d), there are obtained15.4 g of t-butyl 1-N-(benzyloxycarbonyl)-4-t-butoxy-L-glutamoyl!-4-piperidinyl!oxy!acetate.MS (FAB): 535 (M+H)⁺.

b) By hydrogenolyzing 15.4 g of the product of the previous step as inExample 6b), there are obtained 1.5 g of the acetate of t-butyl1-(4-t-butoxy-L-glutamoyl!-4-piperidinyl!oxy!acetate. MS (FAB): 401(M+H)⁺.

c) By coupling 7.5 g of the product of the previous step with 3.9 g ofp-amidinobenzoyl chloride hydrochloride, as in Example 1f), there areobtained 6.9 g of t-butyl 1-N-(p-amidinobenzoyl)-4-t-butoxy-L-glutamoyl!-4-piperidinyl!oxy!acetate.MS (FAB): 547 (M+H)⁺.

EXAMPLE 22

From 2 g of t-butyl (R/S)-1-N-(p-amidinobenzoyl)-L-alanyl!-3-piperidinyl!methoxy!acetate there isobtained, in analogy to Example 1, 0.6 g of the trifluoroacetate of(R/S)-1- N-(p-amidinobenzoyl)-L-alanyl!-3-piperidinyl!methoxy!aceticacid. M.p. 87°-90° C. (ethyl acetate). MS (FAB): 391 (M+H)⁺.

The starting material can be prepared as follows:

a) From rac-3-(hydroxymethyl)piperidine there is obtained, in analogy toExample 1a), rac-N-benzyloxycarbonyl-3-(hydroxymethyl)piperidine. MS(EI): 249 (M)⁺.

b) From the product of a) there is obtained, in analogy to Example 1b),benzyl rac-3- (t-butoxycarbonyl)methoxy!methyl!-1-piperidinecarboxylate.MS (EI): 307 (M-C₄ H₈)⁺.

c) The product of b) is hydrogenated, in analogy to Example 1c), tot-butyl rac-(3-piperidinylmethoxy)acetate. MS (EI): 172 (M-C₄ H₈)⁺.

d) By coupling the product of c) with Z-L-alanine, as in Example 1d),there is obtained benzyl (S)-1- (R/S)-3-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!ethyl!carbamate. MS (EI):434 (M)⁺.

e) By hydrogenating the product of d), as in Example 1e), there isobtained the acetate of t-butyl(R/S)-1-L-alanyl-3-piperidinyl!methoxy!acetate. MS (EI): 285 (M-CH₃)⁺.

f) By coupling the product of e) with p-amidinobenzoyl chloridehydrochloride, as in Example 1f), there is obtained, afterchromatography (silylated silica get RP-18), the desired startingmaterial. MS (FAB): 447 (M+H)⁺.

EXAMPLE 23

From 2.7 g of t-butyl 1-N-(p-amidinobenzoyl)-L-alanyl!-4-(α,α,α-trifluoro-m-tolyl)-4-piperidinyl!oxy!acetatethere is obtained, in analogy to Example 1, 0.7 g of 1-N-(p-amidino-benzoyl)-L-alanyl!-4-(a,a,a-trifluoro-m-tolyl)-4-piperidinyl!-oxy!aceticacid. M.p. above 280° C. (water/methanol). MS (FAB): 521 (M+H)⁺.

The starting material can be prepared as follows:

a) From 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol there is obtained,in analogy to Example 1a), benzyl4-hydroxy-4-(α,α,α-trifluoro-m-tolyl)-1-piperidinecarboxylate. MS (EI):379 (M)⁺.

b) From the product of a) there is obtained, in analogy to Example 1b),benzyl 4-(t-butoxycarbonyl)methoxy!-4-(α,α,α-trifluoro-m-tolyl)-1-piperidinecarboxylate.MS (FAB): 494 (M+H)⁺.

c) By hydrogenating the product of b), as in Example 1e), there isobtained the acetate of4-(α,α,α-trifluoro-m-tolyl)-4-piperidinyl!oxy!acetate. MS (EI): 227(M-C₆ H₁₂ O₃)⁺.

d) By coupling the product of c) with Z-L-alanine, as in Example 1d),there is obtained benzyl (S)-1- 4-(t-butoxycarbonyl)methoxy!-4-(α,α,α-trifluoro-m-tolyl)-1-piperidinyl!carbonyl!ethyl!carbamate.MS (FAB): 565 (M+H)⁺.

e) By hydrogenating the product of d), as in Example 1e), there isobtained the acetate of t-butyl 1-L-alanyl-4-(α,α,α-trifluoro-m-toyly)-4-piperidinyl!oxy!acetate. MS (EI):415 (M-CH₃)⁺.

f) By coupling the product of e) with p-amidinobenzoyl chloridehydrochloride, as in Example 1f), there is obtained the desired startingmaterial. MS (EI): 577 (M+H)⁺.

EXAMPLE 24

A solution of 150 mg of t-butyl 1-1-(p-amidinobenzoyl)-L-propyl!-4-piperidinyl!oxy!acetate in 10 ml ofdichloromethane and 10 ml of trifluoroacetic acid is stirred at roomtemperature for 2 hours and evaporated. The residue is suspended inether and suction filtered. There are obtained 141 mg of 1-1-(p-amidinobenzoyl)-L-propyl!-4-piperidinyl!oxy!acetic acidtrifluoroacetate. M.p. 234°-236° C.

The starting material can be prepared as follows:

a) 4.97 g of 4-cyanobenzoyl chloride, 3:45 g of L-proline and 0.73 g oftetramethylammonium sulphate: in 300 ml of dichloromethane and 150 ml of5% sodium hydrogen carbonate solution are stirred for 48 hours. Theaqueous phase is acidified With 3N sulphuric acid and extracted withethyl acetate. The ethyl acetate phase is washed with saturated sodiumchloride solution, dried and evaporated. Chromatography of the residueon silica gel (RP-18) using water gives 3.70 g of1-(p-cyanobenzoyl)-L-proline. M.p. 80°-85° C.

b) Coupling of 250 mg of 1-(p-cyanobenzoyl)-L-proline with 215 mg oft-butyl 4-piperidinyloxyacetate gives, after chromatography on silicagel with ethyl acetate/methanol (98:2), 300 mg of t-butyl 1-1-(p-cyanobenzoyl)-L-prolyl!-4-piperidinyl!oxy!acetate. MS: 422 (M+H)⁺.

c) Treatment of 1 g of the product of the previous step, as in Example2A)B)C), leads via t-butyl 1-1-(p-thiocarbamoyl)benzoyl!-L-prolyl!-4-piperidinyl!oxy!acetate, m.p.108°-110° C., to 72 mg of the desired acetate, m.p. 100° C.(decomposition).

EXAMPLE 25

Analogously to Example 24, from 150 mg of t-butyl 1-(4R)-1-(p-amidinobenzoyl)-4-benzyloxy-L-prolyl!-4-piperidinyl!oxy!acetatehydroiodide there are obtained, after chromatography on silica gel(RP-18, water/THF 95:5), 72 mg of 1-(4R)-1-(p-amidinobenzoyl)-4-benzyloxy-L-propyl!-4-piperi-dinyl!oxy!aceticacid. M.p. 226°-227° C.

The acetate starting material can be prepared as follows:

a) 1.46 ml of triethylamine are added to a solution of 905 mg of(4R)-hydroxy-L-proline methyl ester and 828 mg of 4-cyanobenzoylchloride in 50 ml of dichloromethane. After stirring, the solution iswashed with saturated sodium chloride solution, dried and evaporated.Chromatography of the residue on silica gel (ethyl acetate/hexane 5:1)gives 810 mg of (4R)-1-(p-cyano-benzoyl)-4-hydroxy-L-proline methylester. M.p. 101°-102° C.

b) 40 μl of trifluoromethanesulfonic acid are added dropwise to asolution of 730 mg of the previous step and 600 μl of benzyltrichloroacetimidate in 5 ml of cyclohexane and 5 ml of dichloromethane.The resulting precipitate is filtered off under suction and the filtrateis washed with 5% sodium hydrogen carbonate solution, dried andevaporated. Chromatography of the residue on silica gel (ethyl acetate)gives 940 mg of (4R)-4-benzyloxyl-1-(p-cyano-benzoyl)-L-proline methylester. MS: 305 (M-59).

c) 880 mg of the product of the previous step and 1.2 ml of 2N lithiumhydroxide solution are stirred in 10 ml of methanol. After removing themethanol, the aqueous residue is acidified with 2.4 ml of 1Nhydrochloric acid and extracted with ethyl acetate. Drying of theorganic phase and evaporation gives 470 mg of(4R)-4-benzyloxy-1-(p-cyanobenzoyl)-L-proline. M.p. 58°-60° C.

d) 450 mg of the product of c) are coupled with 280 mg of t-butyl4-piperidinyloxyacetate in the presence of HBTU. The residue isdissolved in ethyl acetate and the ethyl acetate phase is washed with 5%sodium hydrogen carbonate solution, 1N potassium hydrogen sulphatesolution and saturated sodium chloride solution, dried and evaporated.After chromatography of the residue on silica gel(dichloromethane/methanol 98:2) there are obtained 500 mg of t-butyl 1-(4R)-4-benzyloxy-1-(p-cyanobenzoyl)-prolyl!-4-piperidinyl!oxy!acetate,MS: 548 (M+H)⁺.

e) Treatment of 400 mg of the product of the previous step, as inExample 2A)B)C), leads to 177 mg of the desired acetate. M.p. of thehydroiodide 148°-150° C.

EXAMPLE 26

A solution of 1.60 g of t-butyl 1-(4R)-1-(p-amidino-benzyl)-4-hydroxy-L-prolyl!-4-piperidinyl!oxy!acetatein 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirredat room temperature for 2 hours and evaporated. The residue is dissolvedin ethanol and treated with ether. Suction filtration and drying of theprecipitate gives 1.25 g of 1-(4R)-1-(p-amidino-benzoyl)-4-hydroxy-L-prolyl!-4-piperidinyl!oxy!aceticacid trifluoroacetate. M.p. 220° C.

The acetate starting material can be prepared as follows:

a) Coupling of 14.78 g of (4R)-1-(benzyloxycarbonyl)-4-hydroxy-L-prolinewith 12.0 g of t-butyl 4-piperidinyloxyacetate gives, afterchromatography on silica gel (ethyl acetate/methanol 95:5), 17.83 g oft-butyl 1-(4R)-1-(benzyloxycarbonyl)-4-hydroxy-L-prolyl!-4-piperidinyl!oxy!acetate.MS: 463 (M+H)⁺.

b) Hydrogenation of 17.0 g of the product of the preceding step inethanol in the presence of 2.0 g of Pd/C (10%) gives, after filtrationof the catalyst and concentration, 11.06 g of t-butyl 1-(4R)-4-hydroxy-L-prolyl!-4-piperidinyl!oxy!acetate. MS: 329 (M+H)⁺.

c) Reaction of 2.0 g of the product of the previous step with 1.34 g ofp-amidinobenzoyl chloride according to Example 1f) gives 1.95 g of thedesired acetate.

EXAMPLE 27

A solution of 700 mg of t-butyl 1-1-(p-amidinobenzoyl)-2-piperidinyl!carbonyl!-4-piperidinyl!oxy!acetatein 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirredat room temperature for 3 hours and evaporated. The residue is dissolvedin ethanol and treated with ether. Suction filtration and drying of theprecipitate and chromatography on silica gel (RP-18, water/THF 9:1)gives 111 mg of 1-1-(p-amidino-benzoyl)-2-piperidinyl!carbonyl!-4-piperidinyl!oxyaceticacid. M.p. 233°-234° C.

The acetate starting material is prepared as follows:

a) Coupling of 5.26 g of 1-(benzoyloxycarbonyl)-2-piperidinecarboxylicacid with 4.30 g of t-butyl 4-piperidinyloxyacetate and chromatographyon silica gel (ethyl acetate/hexane 2:1) gives 7.33 g of benzyl 2- 4-(t-butoxycarbonyl)methoxy!piperidino!-carbonyl!-1-piperidinecarboxlate.MS: 461 (M+H)⁺.

b) Hydrogenation of 4.6 g of the product of the previous step in thepresence of 0.4 g of Pd/C (10%) gives, after filtration of the catalystand concentration of the solvent, 3.2 g of t-butyl1-(2-piperidinylcarbonyl)-4-piperidinyl!oxy!acetate. MS: 327 (M+H)⁺.

c) Reaction of 3.26 g of the product of the previous step with 2.49 g ofp-amidinobenzoyl chloride according to Example 1f) gives 1.56 g of thedesired acetate, M.p. 93°-95° C.

EXAMPLE 28

A solution of 130 mg of t-butyl (1RS,2RS,3RS,4SR)-N-(p-amidinobenzoyl)-L-alanyl!amino!-2,3-diacetoxycyclohexyl!-oxy!acetatehydrochloride in 5 ml of dichloromethane and 5 ml of trifluoroaceticacid is stirred at room temperature for 2 hours and concentrated.Suspension of the residue in ether and suction filtration gives 126 mgof (1RS,2RS,3RS,4SR)-4-N-(amidinobenzoyl)-L-alanyl!amino!-2,3-diacetoxycyclohexyl!oxy!-aceticacid trifluoroacetate, MS: 507 (M+H)⁺.

The starting material is prepared as follows:

a) A solution of 4.64 g of cis-4-amino-2-cyclohexen-1-ol, 10.2 g ofN-(benzyloxycarbonyloxy)succinimide and 5.7 ml of triethylamine in DMFis diluted with ether after stirring, washed with saturated sodiumchloride solution, dried and concentrated. Chromatography of the residueon silica gel (ethyl acetate/hexane 2:1) gives 5.62 g of benzyl(1RS,4SR)-4-hydroxy-2-cyclohexene-1-carbamate. MS: 156 (M+H)⁺.

b) 2.1 g of the product of the previous step are reacted with 1.76 ml oft-butyl bromoacetate under phase transfer conditions (30 ml of toluene,30 ml of 50% sodium hydroxide solution, 100 mg of tetrabutylammoniumhydrogen sulphate). After stirring, the organic phase is separated,washed with saturated sodium chloride solution, dried and concentrated.Chromatography of the residue on silica gel (hexane/ethyl acetate 3:1)gives 1.91 g of benzyl (1RS,4SR)-4-(t-butoxycarbonyl)methoxy!-2-cyclohexene-1-carbamate. MS: 333 (M-28)⁺.

c) A solution of 722 mg of the product of the previous step, 280 mg ofN-ethylmorpholine N-oxide and 26 mg of osmium tetroxide in 20 ml ofacetone and 10 ml of water is stirred and then the acetone is removedunder reduced pressure and the aqueous phase is extracted with ether.Washing the organic phase with saturated sodium chloride solution,drying and concentration gives, after chromatography on silica gel(ethyl acetate/hexane 2:1), 476 mg of benzyl (1RS,2RS,3SR,4SR)-4-(t-butoxycarbonyl) methoxy!-2,3-dihydroxycyclohexanecarbamate. MS: 396(M+H)⁺.

d) A solution of 728 g of the product of the previous step in 10 ml ofethanol is hydrogenated in the presence of 100 mg of 10% Pd/C. Then, thecatalyst is filtered off, the filtrate is evaporated and the residue iscoupled with 410 mg of N-benzyloxycarbonyl-L-alanine in 30 ml of THF inthe presence of 697 mg of HBTU and 200 μl of triethylamine. The reactionsolution is diluted with ether, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution, dried and concentrated.Chromatography on silica gel (ethyl acetate/methanol 95:5) gives 521 mgof benzyl (S)-1- (1RS,2SR, 3SR,4SR)-4-(t-butylcarbonyl)methoxy!-2,3-dihydroxy-cyclohexyl!carbamoyl!ethyl!carbamate.MS: 467 (M+H)⁺.

e) Acetylation of 800 mg of the product of the previous step in 10 ml ofacetic anhydride and 10 ml of pyridine and concentration of the reactionsolution gives, after chromatography on silica gel (ethyl acetate/hexane2:1), 670 mg of benzyl (S)-1- (1RS,2SR,3SR, 4SR)-4-(t-butoxycarbonyl)methoxy!-2,3-acetoxycyclohexyl!carbamoyl!ethyl!carbamate.MS: 551 (M+H)⁺.

f) Hydrogenation of 670 mg of the product of the previous step in 10 mlof ethanol in the presence of 100 mg of 10% Pd/C, filtration of thecatalyst and evaporation of the solution gives, after treatment(analogously to Example 1f)) with 329 mg of p-amidinobenzoyl chlorideand chromatography on silica gel (RP-18, water/methanol 9:1), 230 mg ofthe desired starting material. MS: 563 (M+H)⁺.

EXAMPLE 29

220 mg of the product of Example 28 and 300 mg of potassium carbonate in10 ml of methanol are stirred at room temperature and the methanol isthen evaporated. Chromatography on silica gel (RP-18, water/acetonitrile95:5) gives 110 mg of (1RS,2RS,3RS,4SR)-4-N-(p-amidinobenzoyl)-L-alanyl!amino!-2,3-dihydroxycyclohexyl!oxy!aceticacid.

EXAMPLE 30

Treatment of 1.3 g of methyl rac- p-1-(p-cyanobenzoyl)-2-pyrrolidinyl!carbonyl!phenoxy!acetate as describedin Example 2A)B)C) gives, after chromatography (silylated silica gelRP-18, water/methanol gradient) and recrystallization from ethanol, 0.45g of the acetate of methyl rac- p-1-(p-amidinobenzoyl)-2-pyrrolidinyl!carbonyl!phenoxy!acetate. M.p.210°-211° C. MS (FAB): 410 (M+H)⁺.

The starting material can be prepared as follows:

a) By reacting the Grignard reagent from 8.3 g ofp-benzyloxybromobenzene and 0.8 g of magnesium shavings with Z-L-prolineN-methoxymethylamide in THF there are isolated, after chromatography(silica gel, diethyl ether/petroleum ether 1:1), 4.3 g ofrac-1-(benzyloxycarbonyl)-2-(p-benzyloxybenzoyl)-pyrrolidine. MS (EI):211 (C₁₄ H₁₁ O₂)⁺, 204 (C₁₂ H₁₄ O₂)⁺.

b) By hydrogenating 3.3 g of the product of the previous step as inExample 6b) and subsequently reacting with 1.32 g of p-cyanobenzoylchloride in DMF in the presence of triethylamine there are obtained 2.8g of rac-1-(p-cyanobenzoyl)-2-(p-hydroxybenzoyl)-pyrrolidine. M.p.194°-196° C. (ethyl acetate). MS (EI): 320 (M)⁺.

c) Reaction of 2.8 g of the product of the previous step with 1.53 g ofmethyl bromoacetate in DMF in the presence of potassium carbonate gives,after chromatography (silica gel, dichloromethane/methanol 99:1), 1.3 gof the desired starting material. MS (EI): 392 (M)⁺.

EXAMPLE 31

By heating 0.30 g of the product of Example 30 in aqueous acetic acidthere is obtained, after chromatography (silylated silica gel RP-18,water/acetonitrile gradient), 0.11 g of rac-1-(p-amidinobenzoyl)-2-pyrrolidinyl!carbonyl!phenoxy!acetic acid. M.p.above 250° C. MS (FAB): 396 (M+H)⁺.

EXAMPLE 32

By treating 0.85 g of dimethyl 4-1-(p-cyanobenzoyl)-DL-prolyl!-m-phenylene!dioxy!diacetate, as describedin Example 2A)B)C), there is obtained, after chromatography (silylatedsilica gel RP-18, water/methanol gradient) and crystallization fromdiethyl ether, 0.09 g of the acetate of dimethyl 4-1-(p-amidinobenzoyl)DL-prolyl!-m-phenylene!dioxy!diacetate. M.p. 93°-95°C. MS (FAB): 498 (M+H)⁺.

The starting material can be prepared as follows:

a) By reacting the magnesium salt of 4 g of methyl3-hydroxyphenoxyacetate with 5.8 g of Z-L-prolinal and etherifing theproduct with 3.8 g of methyl bromoacetate as described in Example 30c)there are obtained, after chromatography (silica gel, diethylether/petroleum ether 4:1), 7.6 g of dimethyl 4- (RS)-1-(benzyloxycarbonyl)-DL-pyrrolyl!hydroxymethyl!-m-phenylene!dioxy!diacetate,MS (FAB): 488 (M+H)⁺.

b) From 5.3 g of the product of the previous step there are obtained byoxidation with 7.5 ml of Jones reagent in diethyl ether, afterchromatography (silica gel, dichloromethane/methanol 99:1), 2.2 g ofdimethyl 4-1-(benzyloxycarbonyl)-DL-prolyl!-m-phenylene!dioxy!diacetate. MS (EI):485 (M)⁺.

c) By hydrogenating of 2.2 g of the product of the previous step as inExample 6b) and subsequently reacting with 1.0 g of p-cyano benzoylchloride in chloroform in the presence of triethyl-amine there isobtained, after chromatography (silica gel, dichloromethane/methanol99:1), 0.85 g of the desired starting material. MS (EI): 480 (M)⁺.

EXAMPLE 33

From 0.09 g of the product of Example 32 there is obtained by hydrolysisusing aqueous sodium hydroxide in methanol at 50° C. afterneutralization with acetic acid, chromatography (silylated silica gelRP-18, water/acetonitrile gradient) and crystallization from ethanol0.09 g of the monosodium salt of 4-1-(p-amidinobenzoyl)-DL-prolyl!-m-phenylene!dioxy!acetic acid. M.p.241°-242° C. MS (FAB): 492 (M+Na)⁺, 470 (M+H)⁺.

EXAMPLE 34

From 0.47 g of 1-N-(p-amidinobenzoyl)-L-tyrosyl!-4-piperidinyl!oxy!acetic acid (Example14) there is obtained by esterification in ethanol in the presence ofcatalytic amounts of conc. sulphuric acid, after chromatography(LiChroprep RP-18, water/ethanol gradient) 0.3 g of ethyl 1N-(p-amidinobenzoyl)-L-tyrosyl!4-piperidinyl!oxy!acetate hemisulphate,m.p. 182-184° C. (ethanol). MS (ISO=Ionspray): 497 (M+H)⁺.

EXAMPLE 35

From 0.48 g of t-butyl 1- N-5-(1-t-butoxyformamido)pentanoyl!-3-(p-t-butoxyphenyl)-L-alanyl!-4-piperidinyl!oxy!acetatethere is obtained, in analogy to Example 1, after crystallization fromdiethyl ether, 0.2 g of the trifluoroacetate salt of 1-N-(5-aminopentanoyl)-L-tyrosyl!-4-piperidinyl!oxy!-acetic acid, m.p.78°-88° C. (decomposition). α!_(D) ²⁰ =+11.6° (c=0.7, methanol). MS(FAB): 422 (M+H)⁺.

The ester starting material can be prepared as follows:

The reaction of 0.7 g of t-butyl 1-3-(p-t-butoxyphenyl)-L-alanyl!-4-piperidinyl!oxy!acetate (prepared byhydrogenolysis of the produce of Example 14a) with 0.35 g ofN-Boc-5-amino-pentanoic acid in the presence of HBTU andN-methylmorpholine (as in Example 2b) yields 0.55 g of ester startingmaterial, α!_(D) ²⁰ =+1.2° (c=0.4, methanol). MS (FAB): 634 (M+H)⁺.

EXAMPLE 36

From 0.6 g of (S)-3-(p-amidinobenzamido)-3- 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!propyl!t-butylcarbamatethere is obtained in analogy to Example 1, after chromatography(LiChroprep RP-18, water/methanol gradient) and trituration in THF, 0.26g of the trifluoroacetate salt of 1-(S)-2-(p-amidinobenzamido)-4-aminobutanoyl!-4-piperidinyl!oxy!-aceticacid. M.p. above 170° C. (decomposition). α!_(D) ²⁰ =+5.8° (c=0.5,water). MS (EI): 406 (M+H)⁺.

The starting material can be prepared as follows:

a) The reaction of 1.0 g of t-butyl 4-piperidinyloxyacetate with 2.0 gof N² -Fmoc-N⁴ -Boc-(S)-2,4-diaminobutyric acid in the presence of HBTUand Hunig's base as described in Example 2b) yields, afterchromatography (silica gel EtOAc/hexane 1:1.5), 2.2 g of3-t-butyl-1-(fluoren-9-ylmethyl)-(S)-1- 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!trimethylenedicarbamate,MS (FAB): 638 (M+H)⁺.

b) Reaction of 2.3 g of the product of a) with piperidine (20% in DMF)gives, after chromatography (silica gel, ethyl acetate/methanol 4:1),0.65 g of t-butyl (S)-3-amino-3- 4-(t-butoxycarbonyl)methoxy!piperidino!carbonyl!propyl!-carbamate, MS(FAB): 416 (M+H)⁺.

c) By reacting 0.65 g of the product of b) with 0.38 g ofp-amidinobenzoyl chloride hydrochloride (as in Example 1f) there isobtained 0.6 g of the carbamate starting material, MS (FAB): 562 (M+H)⁺.

EXAMPLE 37

From 0.25 g of the acetate salt of t-butyl 1- N-(5-amidino-2-pyridyl)carbonyl!-3-(p-t-butoxyphenyl)-L-alanyl!-4-piperidinyl!oxy!aceticacid there is obtained (as in Example 1), after chromatography(LiChroprep RP-18, water/methanol gradient) and trituration in ethylacetate, 0.12 g of 1- N-(5-amidino-2-pyridyl)carbonyl!-L-tyrosyl!-4-piperidinyl!oxy!acetic acid,m.p. 198°-200° C. (decomposition). MS (FAB): 470 (M+H)⁺.

The starting material can be prepared as follows:

a) Reaction of 2.5 g of t-butyl 1-3-(p-t-butoxyphenyl)-L-alanyl!-4-piperidinyl!oxy!acetate with 0.85 g of5-cyano-2-picolinic acid (as in Example 1d) yields 1.55 g of t-butyl 1-3-(p-t-butoxyphenyl) -N- 5-cyano-2-pyridyl!carbonyl!-L-alanyl!-4-piperidinyl!oxy!acetate. M.p. 122°-123° C. (diethyl ether/petroleumether 4:1). MS (FAB): 565 (M+H)⁺.

b) The successive treatment of 1.43 g of the product of the previousstep as described in Example 2a)b)c) yields 0.98 g of the desiredstarting material. M.p. 183°-186° C. MS (EI): 582 (M+H)⁺.

EXAMPLE 38

Reaction of 0.7 g of ethyl (S)-1-2-(5-cyanopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetateas described in Example 2A)B)C) yields, after crystallization fromwater, 0.1 g of the acetate salt of ethyl (S)-1-2-(5-amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate.M.p. 180°-181° C. (decomposition). MS (ISP): 512 (M+H)⁺

The nitrile starting material can be prepared as follows:

a) Reaction of 7 g of N-Z-L-tyrosine dihydrate with 4.5 g of ethyl4-piperidinyloxyacetate obtained by treating the corresponding t-butylester, Example 1c), with trifluoroacetic acid followed by ethanolichydrochloric acid! as in Example d) yields 6.5 g of ethyl 1-N-(benzyloxycarbonyl)-L-tyrosyl!-4-piperidinyl!oxy!acetate. This productis treated with methyl iodide in DMF in the presence of potassiumcarbonate, whereby there are obtained after chromatography (silica gel,methylene chloride/methanol 99:1) 4.2 g of ethyl (S)-1-2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate,α!_(D) ²⁰ =+1.9° (c=0.8, methanol). MS (ISP): 499 (M+H)⁺.

b) From 4 g of the product of a) there are obtained, in analogy toExample 1e), 3.5 g of ethyl (S)-1-2-amino-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate, MS (EI):365 (M+H)⁺.

c) Coupling of 1.46 g of the product of b) with 0.74 g of5-cyano-2-picolinic acid in accordance with Example 1d) gives, afterchromatography on silica gel (methylene chloride/methanol 40:1), 0.72 gof nitrile starting material, MS (ISP): 495.5 (M+H)⁺.

EXAMPLE 39

By saponifying ethyl (S)-1-2-(5-amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate(Example 38) at pH=12there is obtained, after chromatography (LiChroprepRP-18, water/methanol gradient) and trituration in ethanol, (S)-1-2-(5-amidinopyridin-2-ylcarbonylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyaceticacid. M.p. above 250° C. MS (ISP): 484.4 (M+H)⁺.

EXAMPLE 40

By coupling 1.2 g of ethyl (S)-1-2-amino-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxacetate (Example38b) with 0.77 g of 4-amidinobenzoyl chloride hydrochloride in3-picoline analogously to Example 1f), there is obtained, afterchromatography (LiChroprep RP-18, water/ethanol gradient) andtrituration with ethyl acetate. 0.25 g of the hydrochloride of ethyl(S)-1-2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetatem.p. 105°-107° C. MS (ISP): 511.3 (M+H)⁺.

EXAMPLE 41

By saponifying 0.35 g of the hydrochloride of ethyl (S)-1-2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl!-piperidin-4-yloxyacetate(Example 40) at pH=12 there is obtained, after chromatography(LiChroprep RP-18, water/methanol gradient) and crystallization fromethanol/water, 0.05 g of (S)-1-2-(4-amidinobenzamido)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate,m.p. 191°-192° C. MS (ISP): 483.3 (M+H)⁺.

EXAMPLE 42

From 1.6 g of t-butyl 1-N-(4-amidinobenzoyl)-L-tryptophanyl!piperidin-4-yloxy!acetate there isobtained, in analogy to Example 1, after chromatography (LiChroprepRP-18, water/methanol gradient) and trituration with THF andaceto-nitrile, 0.7 g of 1-N-(4-amidinobenzoyl)-L-tryptophanyl!-piperidin-4-yloxy!acetic acid, m.p.210° C. (decomposition), MS (ISP): 492.2 (M+H)⁺.

The ester starting material is prepared as follows:

a) Reaction of 5.1 g of t-butyl 4-piperidinyloxyacetate (Example 1c)with 8.0 g of Z-Trp-OH in the presence of HBTU and N-methylmorpholine,as described in Example 2b), yields, after chromatography (silica gel,methylene chloride/methanol 20:1), 11.5 g of t-butyl1-(N-benzyloxycarbonyl-L-tryptophanyl)piperidin-4-yloxy!acetate, MS(ISP): 536.0 (M+H)⁺.

b) A solution of 6.6 g of the product of a) in methanol is heated toboiling temperature in the presence of 10 percent Pd/C and ammoniumformate. After filtration and chromatography (silica gel, methylenechloride/methanol 9:1) there are obtained 4.3 g of t-butyl(1-L-tryptophanyl-piperidin-4-yloxy)acetate. MS (EI): 384 (M-NH₃)⁺.

c) By reacting 1.9 g of the product of b) with 1.15 g of4-amidinobenzoyl chloride hydrochloride in pyridine, as described inExample 1f), there are obtained, after chromatography (silica gel,methylene chloride/methanol 7:1), 1.6 g of ester starting material, MS(ISP): 548.3 (M+H)⁺.

EXAMPLE 43

A solution of 3.2 g of t-butyl 1-N-(4-amidinobenzoyl)-4'-hexyloxy-L-phenylalanyl!piperidin-4-yloxy!acetatein formic acid is left at room temperature overnight. Afterconcentration, chromatography (LiChroprep RP-18, water/methanolgradient) and trituration with diethyl ether, there is isolated 0.45 gof 1-N-(4-amidinobenzoyl)-4'-hexyloxy-L-phenylalanyl!piperidin-4-yloxy!aceticacid, m.p. 160° C. (decomposition). α!_(D) ²⁰ =-3.2° (c=0.5, methanol).MS (ISP): 553.2 (M+H)⁺.

The ester starting material is prepared as follows:

a) In analogy to Example 38a), the reaction of 5.6 g of t-butyl 1-N-(benzyloxycarbonyl)-L-tyrosyl!-4-piperidinyl!oxy!acetate with1-iodohexane at 80° C. gives, after chromatography (silica gel,hexane/ethyl acetate 2.5:1), 3.9 g of t-butyl1-(N-benzyloxycarbonyl-4'-hexyloxy-L-phenylalanyl)piperidin-4-yloxy!acetate,MS (EI): 445 (M-Z-NH₂)⁺.

b) By hydrogenating 3.9 g of the product of a) in methanol, analogouslyto Example 1c), there are obtained 2.85 g of t-butyl1-(4'-hexyloxy-L-phenylalanyl)piperidin-4-yloxy!acetate, MS (EI): 462(M)⁺, 445 (M-NH₃)⁺.

c) By reacting 0.5 g of the product of b) with 0.3 g of 4-amidinobenzoylchloride hydrochloride in pyridine, analogously to Example 1f), there isobtained, after chromatography (silica gel, methylene chloride/methanol5:1), 0.7 g of ester starting material, MS (ISP): 609.4 (M+H)⁺.

EXAMPLE 44

A solution of 0.65 g of t-butyl (R,S)-1-2-(4-aminoiminomethyl-N-methylbenzoylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxy!acetatein formic acid is left at room temperature overnight. Afterconcentration and chromatography (LiChroprep RP-18, water/acetonitrilegradient), there is isolated 0.13 g of (R,S)-1-2-(4-aminoiminomethyl-N-methylbenzoylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxy!aceticacid, m.p. 181°-182° C. MS (ISP): 497.1 (M+H)⁺.

The ester starting material is prepared as follows:

a) By coupling 1.38 g of Z-N-Me-Tyr(Me)-OH (J.A.C.S., 112, 1990, 7663)with 0.86 g of t-butyl 4-piperidinyloxyacetate (Example 1c) there areobtained, as described in Example 2b), after chromatography (silica gel,diethyl ether/hexane 5:1), 1.6 g of t-butyl (R,S)-1-2-(N-benzyloxycarbonyl-N-methyl-amine)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxy!-acetate,MS (EI): 541.0 (M+H)⁺.

b) By hydrogenating 1.5 g of the product of a) in methanol, as describedin Example 1c), there are obtained 1.05 g of an oil which is reacteddirectly with 0.58 g of 4-amidinobenzoyl chloride hydrochloride inpyridine as described in Example 1f). After chromatography (silica gel,methylene chloride/methanol 9:1), there is obtained 0.7 g of esterstarting material, M.p. 109°-111° C. MS (ISP): 553.2 (M+H)⁺.

EXAMPLE 45

By esterifying 0.07 g of (R,S)-1-2-(4-aminoiminomethyl-N-methylbenzoylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyaceticacid in ethanol, as described in Example 34, there is obtained, afterchromatography (LiChroprep RP-18, water/ethanol gradient) andtrituration with diethyl ether, 0.056 g of ethyl (R,S)-1-2-(4-aminoiminomethyl-N-methylbenzoylamino)-3-(4-methoxyphenyl)propionyl!piperidin-4-yloxyacetate,m.p. 126°-128° C. MS (ISP): 525.5 (M+H)⁺.

EXAMPLE 46

5 ml of trifluoroacetic acid are added to 100 mg of t-butyl (S)-cis-1-2-(4-amidinobenzoylamino)propionyl!-4-t-butoxycarbonylmethoxy-pyrrolidin-3-yloxyacetatein 5 ml of methylene chloride. After stirring at room temperature, thesolvent is evaporated and the residue is chromatographed on silica gelRP-18 with water/THF (0-50%). There are obtained 73 mg of (S)-cis-1-2-(4-amidinobenzoylamino)propionyl!-4-carboxymethoxy-pyrrolidin-3-yloxyaceticacid. MS: 437 (M+H)⁺.

The ester starting material is prepared as follows:

a) 237 mg of cis-N-benzyloxycarbonylpyrrolidine-3,4-diol, 1 ml oft-butyl bromoacetate and 100 mg of tetrabutyl-ammonium hydrogen sulphatein 10 ml of toluene are stirred with 10 ml of 50% sodium hydroxidesolution under phase transfer conditions. The organic phase is washedwith water and evaporated. Chromatography of the evaporation residue onsilica gel with ethyl acetate/hexane (1:3) gives 354 mg of benzylcis-3,4-bis-t-butoxycarbonylmethoxy-pyrrolidine-1-carboxylate. MS: 354(M-111).

b) 320 mg of the product of the previous step in 10 ml of EtOH arehydrogenated in the presence of 100 mg of 10% Pd/C, the catalyst isfiltered off after 2 hours and the residue in 10 ml of THF is stirredwith 224 mg of N-benzyloxycarbonyl-L-alanine N-hydroxysuccinimide esterin the presence of 100 μl of triethylamine. The reaction solution isdiluted with ether, the organic phase is washed with 1M KHSO₄ solution,dried and evaporated. Chromatography of the residue on silica gel withhexane/ethyl acetate (1:1) gives 260 mg of t-butyl(S)-cis-1-(2-benzyloxycarbonylamino-propionyl)-4-t-butoxycarbonylmethoxypyrrolidin-3-yloxyacetate.MS: 537 (M+H)⁺.

c) 250 mg of the product of the preceding step are hydrogenated in 10 mlof EtOH in the presence of 100 mg of 10% Pd/C, the catalyst is filteredoff after 4 hours and the residue in 10 ml of pyridine is stirred with102 mg of p-amidinobenzoyl chloride hydrochloride. Evaporation of thesolution and chromatography of the residue on silica gel RP-18 withwater/THF (5-30%) gives 143 mg of ester starting material, M.p. 127° C.(d).

EXAMPLE 47

A solution of 150 mg of ethyl (S)-8-2-(4-aminoiminomethyl-benzoylamino)-3-(4-t-butoxyphenyl)propionyl!-8-azabicyclo 3.2.1!octan-endo-3-yloxyacetate hydrochlorideis stirred at room temperature in 5 ml of CH₂ Cl₂ and 2.5 ml oftrifluoroacetic acid and evaporated. With ether the residue givescrystals which are filtered off under suction and dissolved in 5 ml ofEtOH. 40 mg of NaOH dissolved in 1 ml of water are added to the solutionand the mixture is stirred at room temperature. The reaction solution isneutralized with 1N hydrochloric acid and evaporated. Chromatography ofthe residue on silica gel RP-18 with water/THF gives 75 mg of (S)-8-2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl!-8-azabicyclo3.2.1!octan-endo-3-yloxyacetic acid, MS: 495 (M+H)⁺.

The ester starting material is prepared as follows:

a) 2 ml of ethyl diazoacetate in 2 ml of toluene are added at 80° C. toa solution of 1 g of N-benzyloxycarbonyl-nortropine and 20 mg ofrhodium(II) acetate in 3 ml of toluene. After 3.5 hours, the solution isevaporated and the residue is chromatographed on silica gel withhexane/ethyl acetate (20-50%). There are obtained 555 mg of benzylendo-3-ethoxy-carbonylmethoxy-8-azabicyclo 3.2.1!octan-8-carboxylate.MS: 348 (M-H)⁺.

b) A solution of 500 mg of the product of the preceding step in 20 ml ofEtOH is hydrogenated in the presence of 100 mg of 10% Pd/C, the catalystis filtered off after 3 hours and the filtrate is evaporated. Theresidue is dissolved in 10 ml of THF and added to a solution of 828 mgof N-Z-L-Tyr(tBu)-OH, 140 μl of N-methylmorpholine and 569 mg of HBTU in10 ml of THF which has been stirred at 0° C. for 1 hour. After stirring,the reaction solution is evaporated and the residue is chromatographedon silica gel with hexane/ethyl acetate (1:1). There are obtained 650 mgof ethyl (S)-8-2-benzyloxy-carbonylamino-3-(4-t-butoxyphenyl)propionyl!-8-azabicyclo3.2.1!octan-endo-3-yloxyacetate. MS: 567 (M+H)⁺.

c) 600 mg of the product of the previous step are hydrogenated in 20 mlof EtOH in the presence of 100 mg of 10% Pd/C, the catalyst is filteredoff after 16 hours and the residue in 10 ml of pyridine is stirred atroom temperature with 262 mg of p-amidinobenzoyl chloride hydrochloride.Evaporation of the solution and chromatography of the residue on silicagel RP-18 with water/THF (0-50%) gives 198 mg of ester startingmaterial, MS: 579 (M+H)⁺.

EXAMPLE 48

706 mg of butyl (E)- or (Z)-(S)- 3- 2-4-(t-butoxycarbonylimino-di-t-butoxycarbonylaminomethyl)benzoyl-amine!propionylamino!propoxy!acetateare stirred at 20° C. in 1.5 ml of methylene chloride and 1.5 ml oftrifluoroacetic acid. After evaporation of the solvent in a vacuum,evaporation with toluene and crystallization from acetonitrile, thereare obtained 407 mg of butyl (S)- 3- 2-4-(aminoiminomethyl)benzoyl-amine!propionylamino!propoxy!acetatetrifluoroacetate (1:1), M.p. 163°-165° C., α!_(D) ²⁰ =+19° (c=0.5 inmethanol).

The starting material is obtained in the following manner:

a) Acrylonitrile, butyl glycolate and potassium carbonate are heated to60° C. After working up with ethyl acetate and water, the butyl2-cyanoethoxyacetate is distilled. B.p. 100°-120° C., 0.03 mm Hg(bulb-tube).

b) This is hydrogenated in acetic acid on Pd/C and the amine whichthereby results is coupled with N-benzyloxycarbonyl-L-alanine to givebutyl (S)- 3-(2-benzyloxycarbonylaminopropionylamino)propoxy!acetate,m.p. 54°-55° C., α!_(D) ²⁰ =-11.0° (c=0.5 in methanol).

c) By hydrogenation on Pd/C in acetic acid there is obtained therefrombutyl 3-(2-aminopropionylamino)propoxy!acetate which is coupled with p-E/Z!-tri(t-butoxycarbonyl)amidinobenzoic acid to give the startingmaterial. MS: 707 (27 M+H), α!_(D) ²⁰ =+21.4° (c=0.5 in methanol).

EXAMPLE 49

416 mg of butyl (S)- 3- 2-4-(aminoiminomethyl)benzoylamino!propionylamino!propoxy!acetate arestirred at 20° C. in 8.3 ml of 25 percent hydrochloric acid. Thesolution is evaporated and the residue is evaporated with water. FromTHF there are obtained 211 mg of (S)- 3- 2- 4-(aminoimino-methyl)benzoylamino!propionylamino!propoxy!acetic acid hydrochloride as thehydrate (1:1), m.p. 89°-90° C., α!_(D) ²⁰ =+23.4° (c=0.5 in methanol).

EXAMPLE 50

1 g of tert-butyl 1- N-4-(t-butoxycarbonylimino-di-t-butoxycarbonylaminomethyl)benzoyl!-N-(2-methoxyethyl)glycyl!piperidin-4-yloxyacetateis stirred at 20° C. in 3.8 ml of methylene chloride and 3.8 ml oftrifluoroacetic acid. The solvent mixture is evaporated, the residue isevaporated with water, dissolved in ethyl alcohol and adjusted to pH 8with methanolic ammonia solution, whereupon 1- N- 4-(aminoiminomethyl)benzoyl!-N-(2-methoxyethyl)glycyl!piperidin-4-yloxy-acetic acidcrystallizes out as the hydrate (2:1), M.p.>250° C., MS: 421 (100, M+H).

The ester starting material can be obtained in the following manner:

a) N-(2-Methoxyethyl)glycine t-butyl ester is converted with benzylchloroformate in ether and saturated aqueous sodium bicarbonate solutioninto N-benzyloxycarbonyl-N-(2-methoxyethyl)glycine t-butyl ester, MS:324 (82, M+H).

b) This is cleaved in methylene chloride/trifluoroacetic acid toN-benzyloxycarbonyl-N-(2-methoxyethyl)glycine, MS: 267 (1, M).

c) Coupling of the latter with t-butyl piperidin-4-yloxy-acetate leadsto t-butyl 1- N-benzyloxycarbonyl-N-(2-methoxy-ethyl)glycyl!piperidin-4-yloxyacetate, MS: 465 (100, M+H).

d) By catalytic hydrogenation on Pd/C in ethanol there is obtainedtherefrom t-butyl 1- N-(2-methoxyethyl)glycyl!piperidin-4-yloxyacetate,MS: 331 (100, M+H).

e) This is coupled: with4-(t-butoxycarbonylimino-di-t-butoxycarbonylaminomethyl)benzoic acid togive the ester starting material, MS: 777 (70, M+H).

EXAMPLE A

A compound of formula I can be used in a known manner as the activeingredient for the production of tablets of the following composition:

    ______________________________________                                                          Per tablet                                                  ______________________________________                                        Active ingredient       200    mg                                             Microcrystalline cellulose                                                                            155    mg                                             Maize starch            25     mg                                             Talc                    25     mg                                             Hydroxypropylmethylcellulose                                                                          20     mg                                                                     425    mg                                             ______________________________________                                    

EXAMPLE B

A compound of formula I can be used in a known manner as the activeingredient for the manufacture of capsules of the following composition:

    ______________________________________                                                       Per capsule                                                    ______________________________________                                        Active ingredient     100.0  mg                                               Maize starch          20.0   mg                                               Lactose               95.0   mg                                               Talc                  4.5    mg                                               Magnesium stearate    0.5    mg                                                                     220.0  mg                                               ______________________________________                                    

We claim:
 1. A compound of the formula ##STR19## wherein L is a group ofthe formula ##STR20## R is amidino or guanidino, one of X and Y is CH,and the other is N, R⁰ is hydrogen or amidino,t is an integer between 2and 6, R', R" and R'", in the α-aminocarboxylic acid residue of theformula --N(R')C(R",R'")CO-- are hydrogen or N-substituents R' orsidechains R" and R'" of open chain or cyclic, natural or syntheticα-aminocarboxylic acids, wherein a hydroxy or carboxy group present inthe N-substituent R' and sidechains R" and R'" can be etherified or,respectively, esterified or amidated, and amino groups can be C₁₋₆alkanoylated or aroylated, and wherein R' and R" together with the Natom and C atom to which they are attached can form a 4- to 6-memberedring; Q is a group of the formula ##STR21## T is hydrogen or alower-alkyl or phenyl-lower-alkyl group which is cleavable underphysiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof.
 2. A compound according to claim1, wherein L is group L¹, and T in the group Q is hydrogen or alower-alkyl group cleavable under physiological conditions.
 3. Acompound according to claim 1, wherein Q is group Q⁷ in which T ishydrogen.
 4. A compound according to claim 1, wherein--N(R')C(R",R'")Co-- is the N(methoxyethyl)Gly residue.
 5. A compound ofthe formula ##STR22## wherein L⁰ is ##STR23## in which A is anoptionally protected amidino or guanidino group, R⁰¹ is an optionallyprotected amino or guanidino group, one of X and Y is CH and the otheris N,t is an integer between 2 and 6, R', R", R'", E', E" and E'" in theα-aminocarboxylic acid residue of the formula --N(R')C (R", R'")CO-- orN(E')C(E",E'")CO--, are hydrogen or N-substituents R' or E' orsidechains R" and R'" or E" and E'" of open chain or cyclic, natural orsynthetic α-amino-carboxylic acids, wherein a hydroxy or carboxy grouppresent in the N-substituent R' or E' and sidechains R" and R'" or E"and E'" can be etherified or, respectively, esterified or amidated, andamino, groups can be C₁₋₆ alkanoylated or aroylated, and wherein R' andR" or E' and E" together with the N atom and C atom to which they areattached can form a 4- to 6-membered ring; Q and G are each a group ofthe formula T is hydrogen or a lower-alkyl or phenyl-lower-alkyl groupwhich is cleavable under physiological conditions,with the proviso thatwhere R⁰¹ is amino or guanidino or where A is amidino or guanidino, atleast one of E', E", E'" and G contains at least one carboxylic acidester group and/or ether group and/or protected amino group.
 6. Acompound of the formula ##STR24## wherein L is a group of the formula##STR25## R is amidino or guanidino, both X and Y are CH, R⁰ is hydrogenor amidino,t is an integer between 2 and 6, R', R" and R'", in theα-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--, arehydrogen or N-substituents R' or side-chains R" and R'" of open chain orcyclic, natural or synthetic α-aminocarboxylic acids, wherein a hydroxyor carboxy group present in R', R" and R'" can be etherified or,respectively, esterified or amidated, and amino groups present in R', R"and R'" can be C₁₋₆ -alkanoylated or aroylated, and wherein R' and R"together with the N atom and C atom to which they are attached can forma 4- to 6-membered ring; Q is a group of the formula ##STR26## T ishydrogen or a lower-alkyl or phenyl-loweralkyl group which is cleavableunder physiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof.
 7. A compound according to claim6, wherein L is group L¹, and T in the group Q is hydrogen or alower-alkyl group cleavable under physiological conditions.
 8. Acompound according to claim 6, wherein Q is group Q⁷ in which T ishydrogen.
 9. The compound of claim 1, (S)-8-2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl!-8-azabicyclo3.2.1!octan-endo-3-yloxyacetic acid.
 10. A pharmaceutical compositioncomprising an effective amount of a compound of the formula ##STR27##wherein L is a group of the formula ##STR28## R is amidino or guanidino,one of X and Y is CH, and the other is N, R⁰ is hydrogen or amidino,t isan integer between 2 and 6, R', R" and R'", in the α-aminocarboxylicacid residue of the formula --N(R')C(R",R'")CO--, are hydrogen orN-substituents R' or sidechains R" and R'" of open chain or cyclic,natural or synthetic α-aminocarboxylic acids, wherein a hydroxy orcarboxy group present in the N-substituent R' and sidechains R" and R'"can be etherified or, respectively, esterified or amidated, and aminogroups can be C₁₋₆ alkanoylated or aroylated, and wherein R' and R"together with the N atom and C atom to which they are attached can forma 4- to 6-membered ring; Q is a group of the formula ##STR29## T ishydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavableunder physiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof and a pharmaceutically inertcarrier.
 11. The pharmaceutical composition according to claim 10,wherein L is group L¹ and T in the group Q is hydrogen or a lower-alkylgroup cleavable under physiological conditions.
 12. The pharmaceuticalcomposition according to claim 10, wherein Q is group Q⁷ in which T ishydrogen.
 13. The pharmaceutical composition according to claim 10,wherein --N(R')C(R",R'")CO-- is the N(methoxyethyl)Gly residue.
 14. Apharmaceutical composition comprising an effective amount of a compoundof the formula ##STR30## wherein L is a group of the formula ##STR31## Ris amidino or guanidino, both X and Y are CH, R⁰ is hydrogen oramidino,t is an integer between 2 and 6, R', R" and R'", in theα-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--, arehydrogen or N-substituents R' or side-chains R" and R'" of open chain orcyclic, natural or synthetic α-aminocarboxylic acids, wherein a hydroxyor carboxy group present in R', R" and R'" can be etherified or,respectively, esterified or amidated, and amino groups present in R', R"and R'" can be C₁₋₆ -alkanoylated or aroylated, and wherein R' and R"together with the N atom and C atom to which they are attached can forma 4- to 6-membered ring; ##STR32## T is hydrogen or a lower-alkyl orphenyl-lower alkyl group which is cleavable under physiologicalconditions,as well as hydrates or solvates and physiologically usablesalts thereof and a pharmaceutically inert carrier.
 15. Thepharmaceutical composition according to claim 14, wherein L is group L¹,and T in the group Q is hydrogen or a lower-alkyl group cleavable underphysiological conditions.
 16. A method for the control or prevention ofblood platelet thrombi, thrombosis, stroke, cardiac infarct,inflammation, or arteriosclerosis, comprising administering a compoundof the formula ##STR33## wherein L is a group of the formula ##STR34## Ris amidino or guanidino, one of X and Y is CH, and the other is N, R⁰ ishydrogen or amidino,t is an integer between 2 and 6, R', R" and R'", inthe α-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--,are hydrogen or N-substituents R' or sidechains R" and R'" of open chainor cyclic, natural or synthetic α-aminocarboxylic acids, wherein ahydroxy or carboxy group present in the N-substituent R' and sidechainsR" and R'" can be etherified or, respectively, esterified or amidated,and amino groups can be C₁₋₆ alkanoylated or aroylated, and wherein R'and R" together with the N atom and C atom to which they are attachedcan form a 4- to 6-membered ring; Q is a group of the formula ##STR35##T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which iscleavable under physiological conditions,as well as hydrates or solvatesand physiologically usable salts thereof.
 17. The method of claim 16,wherein L is group L¹ and T in the group Q is hydrogen or a lower-alkylgroup cleavable under physiological conditions.
 18. The method of claim16, wherein Q is group Q⁷ in which T is hydrogen.
 19. The method ofclaim 16, wherein --N(R')C(R",R'")CO-- is the N(methoxy-ethyl)Glyresidue.
 20. A method for inhibiting fibrinogen-, fibronectin- and theWillebrand factor dependent-binding of tumor cells to a fibrinogenreceptor of blood platelets comprising administering a compound of theformula ##STR36## wherein L is a group of the formula ##STR37## R isamidino or guanidino, one of X and Y is CH, and the other is N, R⁰ ishydrogen or amidino,t is an integer between 2 and 6, R', R" and R'", inthe α-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--,are hydrogen or N-substituents R' or sidechains R" and R'" of open chainor cyclic, natural or synthetic α-aminocarboxylic acids, wherein ahydroxy or carboxy group present in the N-substituent R' and sidechainsR" and R'" can be etherified or, respectively, esterified or amidated,and amino groups can be C₁₋₆ alkanoylated or aroylated, and wherein R'and R" together with the N atom and C atom to which they are attachedcan form a 4- to 6-membered ring; Q is a group of the formula ##STR38##T is hydrogen or a lower-alkyl or phenyl-lower-alkyl group which iscleavable under physiological conditions,as well as hydrates or solvatesand physiologically usable salts thereof.
 21. A method of wound healingcomprising administering a compound of the formula ##STR39## wherein Lis a group of the formula ##STR40## R is amidino or guanidino, one of Xand Y is CH, and the other is N, R⁰ is hydrogen or amidino,t is aninteger between 2 and 6, R', R" and R'", in the α-aminocarboxylic acidresidue of the formula --N(R')C(R",R'")CO--, are hydrogen orN-substituents R' or sidechains R" and R'" of open chain or cyclic,natural or synthetic α-aminocarboxylic acids, wherein a hydroxy orcarboxy group present in the N-substituent R' and sidechains R" and R'"can be etherified or, respectively, esterified or amidated, and aminogroups can be C₁₋₆ alkanoylated or aroylated, and wherein R' and R"together with the N atom and C atom to which they are attached can forma 4- to 6-membered ring; Q is a group of the formula ##STR41## T ishydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavableunder physiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof.
 22. A method for treatingosteoporosis comprising administering a compound of the formula##STR42## wherein L is a group of the formula ##STR43## R is amidino orguanidino, one of X and Y is CH, and the other is N, R⁰ is hydrogen oramidino,t is an integer between 2 and 6, R', R" and R'", in theα-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--, arehydrogen or N-substituents R' or sidechains R" and R'" of open chain orcyclic, natural or synthetic α-aminocarboxylic acids, wherein a hydroxyor carboxy group present in the N-substituent R' and sidechains R" andR'" can be etherified or, respectively, esterified or amidated, andamino groups can be C₁₋₆ alkanoylated or aroylated, and wherein R' andR" together with the N atom and C atom to which they are attached canform a 4- to 6-membered ring; Q is a group of the formula ##STR44## T ishydrogen or a lower-alkyl or phenyl-lower-alkyl group which is cleavableunder physiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof.
 23. A method for the controland/or prevention of blood platelet thrombi, thrombosis, stroke, cardiacinfarct, inflammation, or arteriosclerosis, comprising administering acompound of the formula ##STR45## wherein L is a group of the formula##STR46## R is amidino or guanidino, both X and Y are CH, R⁰ is hydrogenor amidino,t is an integer between 2 and 6, R', R" and R'", in theα-aminocarboxylic acid residue of the formula --N(R')C(R",R'")CO--, arehydrogen or N-substituents R' or side-chains R" and R'" of open chain orcyclic, natural or synthetic α-aminocarboxylic acids, wherein a hydroxyor carboxy group present in R', R" and R'" can be etherified or,respectively, esterified or amidated, and amino groups present in R', R"and R'" can be C₁₋₆ -alkanoylated or aroylated, and wherein R' and R"together with the N atom and C atom to which they are attached can forma 4- to 6-membered ring; Q is a group of the formula ##STR47## T ishydrogen or a lower-alkyl or phenyl-lower alkyl group which is cleavableunder physiological conditions,as well as hydrates or solvates andphysiologically usable salts thereof.